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Pharmacology An Introduction
6 th edition Henry Hitner, Ph.D. Professor Emeritus Department of Neuroscience, Physiology, Pharmacology Philadelphia College of Osteopathic Medicine Philadelphia, Pennsylvania Adjunct Professor, Pharmacology Physician Assistant Program Drexel University Philadelphia, Pennsylvania
Barbara Nagle, Ph.D. President Clinical Research Development and Education III Associates Bryn Mawr, Pennsylvania TM
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TM
PHARMACOLOGY: AN INTRODUCTION Published by McGraw-Hill, a business unit of The McGraw-Hill Companies, Inc., 1221 Avenue of the Americas, New York, NY, 10020. Copyright © 2012 by The McGraw-Hill Companies, Inc. All rights reserved. Previous editions © 1994, 1999, and 2005. No part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written consent of The McGraw-Hill Companies, Inc., including, but not limited to, in any network or other electronic storage or transmission, or broadcast for distance learning. Some ancillaries, including electronic and print components, may not be available to customers outside the United States. This book is printed on acid-free paper. 1 2 3 4 5 6 7 8 9 0 DOW/DOW 1 0 9 8 7 6 5 4 3 2 1 ISBN 978-0-07-352086-5 MHID 0-07-352086-1 Vice president/Editor in chief: Elizabeth Haefele Vice president/Director of marketing: John E. Biernat Publisher: Kenneth S. Kasee Jr. Director of development: Sarah Wood Managing Developmental Editor: Christine Scheid Senior developmental editor: Patricia Hesse Editorial coordinator: Parissa DJangi Marketing manager: Mary B. Haran Lead digital product manager: Damian Moshak Director, Editing/Design/Production: Jess Ann Kosic Project manager: Marlena Pechan Buyer II: Debra R. Sylvester Senior designer: Marianna Kinigakis Senior photo research coordinator: John C. Leland Photo researcher: Danny Meldung Digital production coordinator: Brent dela Cruz Outside development house: Andrea Edwards, Triple SSS Press Cover design: Alexa R. Viscius & Anna Kinigakis Interior design: Jessica M. Lazar Typeface: 11/13 Perpetua Regular Compositor: Laserwords Private Limited Printer: R. R. Donnelley Cover credit: Image Copyright © 2010, Nucleus Medical Media, Inc. All Rights Reserved. Credits: The credits section for this book begins on page 855 and is considered an extension of the copyright page. Library of Congress Cataloging-in-Publication Data Hitner, Henry. Pharmacology: an introduction/Henry Hitner, Barbara Nagle. —6th ed. p.; cm. Includes bibliographical references and index. ISBN-13: 978-0-07-352086-5 (alk. paper) ISBN-10: 0-07-352086-1 (alk. paper) 1. Pharmacology. I. Nagle, Barbara T. II. Title. [DNLM: 1. Pharmacological Phenomena. 2. Drug Therapy. QV 4] RM300.H57 2012 615’.1—dc22
2010043213
The Internet addresses listed in the text were accurate at the time of publication. The inclusion of a Web site does not indicate an endorsement by the authors or McGraw-Hill, and McGraw-Hill does not guarantee the accuracy of the information presented at these sites. WARNING NOTICE: The clinical procedures, medicines, dosages, and other matters described in this publication are based upon research of current literature and consultation with knowledgeable persons in the field. The procedures and matters described in this text reflect currently accepted clinical practice. However, this information cannot and should not be relied upon as necessarily applicable to a given individual’s case. Accordingly, each person must be separately diagnosed to discern the patient’s unique circumstances. Likewise, the manufacturer’s package insert for current drug product information should be consulted before administering any drug. Publisher disclaims all liability for any inaccuracies, omissions, misuse, or misunderstanding of the information contained in this publication. Publisher cautions that this publication is not intended as a substitute for the professional judgment of trained medical personnel.
www.mhhe.com
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Brief Contents About the Authors Preface
xvii
xviii
What Every Student Needs to Know
xxii
1
Pharmacology: An Introduction
4
2
Pharmacokinetics and Factors of Individual Variation
3
Geriatric Pharmacology
4
Math Review and Dosage Calculations
5
Introduction to the Autonomic Nervous System
6
Drugs Affecting the Sympathetic Nervous System
7
Drugs Affecting the Parasympathetic Nervous System
8
Drugs Affecting the Autonomic Ganglia
9
Skeletal Muscle Relaxants
17
36 45 60 72 91
107
115
10
Local Anesthetics
131
11
Introduction to the Central Nervous System
12
Sedative-Hypnotic Drugs and Alcohol 157
13
Antipsychotic and Antianxiety Drugs
14
Antidepressants, Psychomotor Stimulants, and Lithium
15
Psychotomimetic Drugs of Abuse
16
Antiepileptic Drugs
17
Antiparkinson Drugs
229
18
General Anesthetics
243
19
Opioid Analgesics
20
Nonopioid Analgesics, Nonsteroidal Antiinflammatories, and Antigout Drugs
148
173 188
203
216
268
292
iii
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21
Review of Cardiac Physiology and Pathology
322
22
Treatment of Heart failure
23
Antiarrhythmic Drugs 347
24
Antianginal Drugs 363
25
Diuretics 376
26
Antihypertensive Drugs 398
27
Anticoagulants and Coagulants
28
Nutrition and Therapy 436
29
Hypolipidemic Drugs 459
30
Antianemics
31
Antihistaminic Drugs and Mast Cell Release Inhibitors
32
Respiratory Pharmacology, Treatment of Asthma, and COPD 520
33
Therapy of Gastrointestinal Disorders: Peptic Ulcers, GERD,
331
415
480 500
and Vomiting 538 34
Agents That Affect Intestinal Motility
567
35
Introduction to the Endocrine System
36
Adrenal Steroids 599
37
Gonadal Hormones, Oral Contraceptives, and Erectile
586
Dysfunction Drugs 617 38
Drugs Affecting the Thyroid and Parathyroid Glands and Bone Degeneration
644
39
Pancreatic Hormones and Antidiabetic Drugs
40
Posterior Pituitary Hormones: Antidiuretic Hormone and Oxytocin
665
697
41
Antibacterial Agents
42
Antifungal and Antiviral Drugs 735
43
Parasitic Infections: Antiprotozoal and Anthelmintic Drugs
44
Antiseptics and Disinfectants
45
Antineoplastic Agents
46
Immunopharmacology 821 Glossary
712
769
786
802
835
Appendix A Latin Abbreviations Used in Medicine
850
Appendix B Abbreviations and Symbols Commonly Used in Medical Notations Index iv
851
857
Brief Contents
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Table of Contents PART 1 General Concepts
3
CHAPTER 1 Pharmacology: An Introduction 4 Drug Sources
6
Terminology Related to Drug Effects 6 Basic Concepts in Pharmacology
7
Dose-Response Curve 8 Drug Safety
9
Drug Nomenclature Drug References Chapter Review
10
10 13
CHAPTER 2 Pharmacokinetics and Factors of Individual Variation 17 Drug Forms
18
Routes of Administration Drug Absorption
19
20
Drug Distribution 21 Drug Metabolism
22
Drug Excretion 22 Half-Life
23
Blood Drug Levels
24
Bioavailability 24 Factors of Individual Variation 25 Pharmacokinetic Considerations for Pediatrics Drug Interactions
26
28
Terminology Associated with Chronic Drug Use and Abuse Chapter Review
28
30
CHAPTER 3 Geriatric Pharmacology Drug Use in the Elderly Drug Absorption
36 37
37
Drug Metabolism and Excretion
38
Effects of Age on Drug Response 38 Drug Compliance in the Elderly Chapter Review
40
42
v
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CHAPTER 4 Math Review and Dosage Calculations 45 Fractions, Decimals, and Percents
46
Dosage Calculations 48 Systems of Measurement Calculating Dosages
48
50
Pediatric Dosage Calculations Monitoring IV Infusion Rates
51
52
Chapter Review 54
PART 2 Pharmacology of the Peripheral Nervous System 59 CHAPTER 5 Introduction to the Autonomic Nervous System Nervous System Organization
60
61
Overview of the ANS 62 Parasympathetic and Sympathetic Divisions Cholinergic and Adrenergic Receptors Chapter Review
62
67
68
CHAPTER 6 Drugs Affecting the Sympathetic Nervous System
72
Adrenergic Nerve Endings 73 Adrenergic Receptors 74 Alpha-Adrenergic Drugs 75 Beta-Adrenergic Drugs 77 Alpha-Adrenergic Blocking Drugs 79 Beta-Adrenergic Blocking Drugs
80
Adrenergic Neuronal Blocking Drugs 82 Chapter Review
86
CHAPTER 7 Drugs Affecting the Parasympathetic Nervous System 91 Cholinergic Nerve Activity Cholinergic Receptors Cholinergic Drugs
92
92
94
Clinical Indications for Anticholinesterase Drugs Anticholinergic Drugs
97
99
Preferred Treatment for Selected Conditions 101 Chapter Review
vi
102
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CHAPTER 8 Drugs Affecting the Autonomic Ganglia 107 Ganglionic Stimulants
108
Ganglionic Blockers 110 Adverse Effects of Ganglionic Blockers 110 Chapter Review
112
CHAPTER 9 Skeletal Muscle Relaxants
115
Skeletal Muscle Relaxants
117
Clinical Indications 117 Peripherally Acting Skeletal Muscle Relaxants
117
Adverse and Toxic Effects 120 Direct-Acting Skeletal Muscle Relaxants 122 Centrally Acting Skeletal Muscle Relaxants (Spasmolytics) Chapter Review
122
127
CHAPTER 10 Local Anesthetics 131 Mechanism of Action Pharmacology
132
133
Routes of Administration 134 Adverse Effects 137 Clinical Applications and Preferred Treatment
138
Chapter Review 141
PART 3 Pharmacology of the Central Nervous System 147 CHAPTER 11 Introduction to the Central Nervous System
148
Structural and Functional Features of the Brain 149 Diencephalon and Brainstem
150
Cerebellum 151 Spinal Cord 151 Functional Components Chapter Review
151
153
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CHAPTER 12 Sedative - Hypnotic Drugs and Alcohol 157 Sleep Cycle
159
Mechanism of Action of Sedative-Hypnotic Drugs Barbiturate Sedatives and Hypnotics
160
160
Benzodiazepines 163 Miscellaneous Hypnotic Drugs Alcohol
164
166
Chapter Review
169
CHAPTER 13 Antipsychotic and Antianxiety Drugs 173 Antipsychotic Drugs Antianxiety Drugs Chapter Review
174
179 184
CHAPTER 14 Antidepressants, Psychomotor Stimulants, and Lithium Types of Depression
188
189
Drugs Used to Treat Depression
190
Monoamine Oxidase Inhibitors
194
Psychomotor Stimulants
195
Lithium 196 Preferred Therapy for Depression, Mania, and Bipolar Disorder 197 Chapter Review
198
CHAPTER 15 Psychotomimetic Drugs of Abuse LSD-Type Hallucinogens
204
Psychomotor Stimulants
205
203
Miscellaneous Psychotomimetic Drugs Chapter Review
209
212
CHAPTER 16 Antiepileptic Drugs 216 Types of Epilepsy 217 Drugs Effective for Both Generalized Tonic-Clonic and Partial Seizures
218
Drugs Effective Primarily for Partial Seizures 222 Drugs Used in the Treatment of Absence Seizures 222 Treatment of Status Epilepticus 223 Preferred Therapy for Epileptic Seizures 223 Chapter Review
viii
225
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CHAPTER 17 Antiparkinson Drugs 229 Neurotransmitters Affecting the Basal Ganglia 230 Levodopa (Dopar, Larodopa)
230
Enzyme Inhibitors That Increase the Actions of Levodopa 234 Dopamine Receptor Agonists Miscellaneous Drugs
235
236
Preferred Therapy for Parkinson’s Disease Chapter Review
237
238
CHAPTER 18 General Anesthetics 243 General Anesthesia
245
General Anesthetics
247
Mechanism of Action 253 Physiological Effects of Anesthetics 254 Adjuncts to General Anesthesia
257
Special Considerations and Cautions Preferred Use of Anesthetics Chapter Review
261
263
264
CHAPTER 19 Opioid Analgesics 268 Pain
270
Opioid Analgesics 271 Drug Administration 277 Adverse Effects, Tolerance, and Physical Dependence 279 Opioid Antagonists and Respiratory Depression Opioid Antitussives Drug Interactions Chapter Review
281
282 283
287
CHAPTER 20 Nonopioid Analgesics, Nonsteroidal Antiinflammatories, and Antigout Drugs 292 Inflammation and Antiinflammatory Drug Action
293
Nonopioid Analgesics: Salicylates (Aspirin) 296 Acetaminophen
303
Other Nonsteroidal Antiinflammatory Drugs (NSAIDS) Drugs Useful in Treating Gout Drug Interactions
311
Preferred Therapy
313
Chapter Review
305
309
315 Table of Contents
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PART 4 Pharmacology of the Heart 321 CHAPTER 21 Review of Cardiac Physiology and Pathology 322 Cardiac Function
323
Main Diseases of the Heart Chapter Review
326
327
CHAPTER 22 Treatment of Heart Failure
331
Chronic Heart Failure (CHF) Diuretic Therapy of CHF
332
334
Vasodilator Therapy of CHF
335
Use of Adrenergic Beta-Blockers in CHF 336 Cardiac Glycosides
337
Chapter Review 342
CHAPTER 23 Antiarrhythmic Drugs 347 Types of Arrhythmias
348
Class 1 Antiarrhythmic Drugs: Sodium Channel Blockers Class 2 Antiarrhythmic Drugs: Beta-Blockers
351
354
Class 3 Antiarrhythmic Drugs: Potassium Channel Blockers Class 4 Antiarrhythmic Drugs: Calcium Channel Blockers
355 356
Special Considerations and Preferred Therapy for Selected Arrhythmias 357 Chapter Review
359
CHAPTER 24 Antianginal Drugs 363 Classification of Angina Pectoris 364 Nitrates
365
Beta-Adrenergic Blocking Drugs Calcium Channel Blockers
367
368
Preferred Therapy for Treatment of Angina Pectoris Chapter Review
x
369
370
Table of Contents
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PART 5 Pharmacology of the Vascular and Renal Systems
375
CHAPTER 25 Diuretics 376 Clinical Indications and Renal Function
378
Renal Physiology 378 Conditions Associated with Renal Dysfunction Osmotic Diuretics
382
383
Carbonic Anhydrase Inhibitors
384
Thiazide and Thiazide-Like Diuretics Organic Acid Diuretics
385
387
Potassium-Sparing Diuretics
387
ADH Antagonists and Miscellaneous Diuretics
389
Special Considerations 390 Drug Interactions and Incompatibilities Preferred Treatment Chapter Review
392
392
394
CHAPTER 26 Antihypertensive Drugs 398 Physiological Factors Controlling Blood Pressure Diuretics
399
401
Drugs That Reduce Sympathetic Activity 404 Vasodilator Drugs
405
Drugs That Reduce the Activity of Angiotensin II Treatment of Hypertensive Crisis
408
Patient Education and Monitoring
408
Preferred Therapy for Treatment of Hypertension Chapter Review
406
408
410
CHAPTER 27 Anticoagulants and Coagulants Coagulation
415
416
Anticoagulant Mechanisms of Action
418
Heparins 419 Oral Anticoagulant: Warfarin Sodium (Coumadin)
421
Antiplatelet Drugs 423 Special Considerations and Contraindications with Anticoagulants Monitoring Coagulation
424
424
Fibrinolytic/Thrombolytic Drugs 428
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Preferred Treatment with Anticoagulants and Thrombolytics Coagulants/Hemostatics Chapter Review
429
430
432
CHAPTER 28 Nutrition and Therapy 436 Nutrients
437
Vitamins 442 Fat-Soluble Vitamins
443
Water-Soluble Vitamins Body Water Minerals
447
449
449
Chapter Review 454
CHAPTER 29 Hypolipidemic Drugs 459 Atherosclerosis and Arterial Disease Hypolipidemic/Antilipemic Drugs Other Hypolipidemic Drugs Preferred Therapy
461
465
469
471
Contraindications and Pregnancy Drug Interactions
472
472
Chapter Review 475
CHAPTER 30 Antianemics
480
Causes of Anemia
481
Iron Deficiency Anemia 482 Cobalamin Deficiency Anemia 487 Folic Acid Deficiency 488 Erythropoietin Stimulating Agents Chapter Review
490
493
PART 6 Drugs That Affect the Respiratory System 499 CHAPTER 31 Antihistaminic Drugs and Mast Cell Release Inhibitors 500 Action of Histamine
502
Mast Cell Release Inhibitors
504
Antihistamine H1 Antagonists 507 Chapter Review 515
xii
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CHAPTER 32 Respiratory Pharmacology, Treatment of Asthma, and COPD Respiratory Diseases
520
521
Role of the Autonomic Nervous System
524
Bronchodilator Drugs 525 Antiinflammatory Drugs Antiallergic Agents
528
530
Mucolytics and Expectorants 530 Preferred Therapy for Asthma and COPD 531 Chapter Review 532
PART 7 Pharmacology of the GI Tract
537
CHAPTER 33 Therapy of Gastrointestinal Disorders: Peptic Ulcers, GERD, and Vomiting 538 Digestion and Ulcer Production 539 Management of Ulcers
542
Management of Gastroesophageal Reflux Disease (GERD) Antisecretory Drugs: Receptor-Mediated Drug Action
543
543
Acid Neutralization: Antacids 553 Barrier Enhancers: Sucralfate Management of Emesis
555
556
Chapter Review 563
CHAPTER 34 Agents That Affect Intestinal Motility Bowel Function
567
569
Antidiarrheals 569 Laxatives and Cathartics
573
Chapter Review 579
PART 8 Pharmacology of the Endocrine System 585 CHAPTER 35 Introduction to the Endocrine System Endocrine System
586
587
Hypothalamic-Pituitary Axis
589
Anterior Pituitary Growth Hormone
591
Chapter Review 595 Table of Contents
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CHAPTER 36 Adrenal Steroids
599
Regulating Adrenocorticoid Secretions Glucocorticoids
600
602
Mineralocorticoids 609 Special Considerations Drug Interactions
610
611
Chapter Review 613
CHAPTER 37 Gonadal Hormones, Oral Contraceptives, and Erectile Dysfunction Drugs
617
Female Sex Hormones 619 Hormonal Replacement Therapy (HRT) 622 Fertility Drugs
630
Male Sex Hormones (Androgens) Erectile Dysfunction Chapter Review
632
636
640
CHAPTER 38 Drugs Affecting the Thyroid and Parathyroid Glands and Bone Degeneration Thyroid Function, Pharmacology, and Disorders Parathyroid Hormones
644
646
652
Degenerative Bone Disease: Osteoporosis
654
Chapter Review 660
CHAPTER 39 Pancreatic Hormones and Antidiabetic Drugs 665 Pancreatic Endocrine Function Diabetes Mellitus
667
670
Treatment of Diabetes
672
Parenteral Antidiabetic Drugs: Insulin
673
Oral Antidiabetic Drugs: Secretagogues, Hypoglycemics Other Oral Antihyperglycemic Drugs Chapter Review
682
686
692
CHAPTER 40 Posterior Pituitary Hormones: Antidiuretic Hormone and Oxytocin 697 Posterior Pituitary Hormones
698
Antidiuretic Hormone 699 Drugs Affecting Uterine Muscle 702 Tocolytics
703
Chapter Review
xiv
705
Table of Contents
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PART 9 Pharmacology of Infectious Diseases
711
CHAPTER 41 Antibacterial Agents
712
Morphology of Bacteria Chemotherapy Penicillins
713
714
716
Cephalosporins
719
Aminoglycosides Tetracyclines
721
722
Sulfonamides
723
Macrolide Antibiotics
724
Fluoroquinolone Antimicrobials
725
Miscellaneous Antimicrobial Drugs Drugs Used to Treat Tuberculosis
726
727
Preferred Therapy for Selected Infections
728
Chapter Review 730
CHAPTER 42 Antifungal and Antiviral Drugs 735 Fungal Infections and Antifungal Drugs 737 Viral Diseases 748 Antiviral Drugs
754
Drug Interactions Chapter Review
763 765
CHAPTER 43 Parasitic Infections: Antiprotozoal and Anthelmintic Drugs 769 Protozoal Infections Malaria
770
771
Dysentery
774
Other Protozoal Infections Anthelmintic Drugs
776
778
Chapter Review 781
CHAPTER 44 Antiseptics and Disinfectants 786 Antisepsis and Disinfection
787
Antiseptics and Disinfectants
793
Chapter Review 797
Table of Contents
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PART 10 Antineoplastics and Drugs Affecting the Immune System 801 CHAPTER 45 Antineoplastic Agents
802
Types of Cancer
803
Alkylating Drugs
805
Antimetabolites
808
Drugs Derived from Natural Products 810 Hormone Antagonists 811 New Approaches to Cancer Chemotherapy
814
Chapter Review 816
CHAPTER 46 Immunopharmacology Immune System
821
822
Immunosuppressive Drugs
825
Immunomodulating Drugs 828 Chapter Review 830
Glossary
835
Appendix A Latin Abbreviations Used in Medicine
850
Appendix B Abbreviations and Symbols Commonly Used in Medical Notations
851
Index 857
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About the Authors Henry Hitner
earned a Bachelor of Science degree in biology from Moravian College in Bethlehem, Pennsylvania, and spent several years working in the pharmaceutical industry, first as a research assistant in toxicology for Wyeth Laboratories and then as a research pharmacologist for National Drug Company, both in Philadelphia. During this time he earned a Master of Education degree in biology from West Chester University. He attended graduate school at Hahnemann Medical College in Philadelphia, where he earned a Ph.D. in pharmacology. Dr. Hitner then went into academia, where he held numerous faculty positions, first as an instructor of biology and allied health sciences at Montgomery County Community College, followed by 30 years of teaching and research at the Philadelphia College of Osteopathic Medicine (PCOM). At PCOM he served as professor and vice chair of the neuroscience, physiology, and pharmacology department. Other positions included director of the animal facility and chair of the institutional animal care and utilization committee. Professional memberships included the Sigma Xi Scientific Research Society and the American Society for Pharmacology and Experimental Therapeutics. He was the recipient of the Lindback Foundation Award for Distinguished Teaching and a Mentor Award from the National Student Association. Henry and his wife Carlotta enjoy traveling, the beach, and time spent with family and their seven grandchildren.
Barbara Nagle
earned a Master of Science and doctorate at Hahnemann Medical College and University in the department of pharmacology. Following postdoctoral training in ocular pharmacology at Will’s Eye Hospital, Philadelphia, she taught pharmacology and physiology to medical students at the Philadelphia College of Osteopathic Medicine (PCOM) and to nursing students at Widener University. After several years in academia, she moved into the pharmaceutical industry as Director of Clinical Information and later Vice President of Clinical Research, Training and Quality Assurance. She has been part of the research effort to bring products through clinical development to FDA approval such as gastric acid suppressants (antihistamines), beta-blockers, anti-infectives, muscle relaxants, and oral contraceptives. The most recent affiliation was with Endo Pharmaceuticals in pain management research prior to her current activities as consultant and educator. She has served as International Director of Drug Development Training and Medical Education for BioPharm. Professional memberships include the Sigma Xi Scientific Research and American Medical Writers Association. Barbara is a freelance photographer, traveler, and silk painter.
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Preface The sixth edition of Pharmacology: An Introduction has been completely updated and redesigned, but the aim of this textbook remains what it has always been: to present a clear understanding of the basic concepts of pharmacology to the beginning student. Pharmacology is a complex subject that requires basic knowledge in many different scientific disciplines, particularly anatomy, physiology, and pathology. Health professions students often have limited exposure to these subjects and one of the objectives of our text is to provide the necessary background information and to refresh the student’s memory of previously learned material through which the therapeutic action of drugs can be clearly understood. The goal of this text is to explain the mechanisms of action of drugs. Understanding how drugs produce their effects allows the student to better understand the different pharmacologic actions and adverse effects that drugs produce. Pharmacology: An Introduction is designed for a variety of health professions programs requiring an understanding of pharmacology. The book presents a basic rationale for understanding current drug therapy. The drug information and chapter features are designed to be applicable and adaptable to many different educational programs. Personnel in the health and nursing professions spend much of their working time in direct contact with patients—observing, treating, and administering to the countless requirements and demands that constitute effective and responsible patient care. Therefore, it is important that students in health professions acquire a sound basic understanding of pharmacology as it relates to their particular needs. New scientific discoveries and advances in the understanding of disease provide a continual introduction and approval of new drugs. At the same time, older drug therapies and drugs that cause serious adverse effects or other problems are eliminated. New advances in genetics and molecular biology have allowed the development of monoclonal antibodies and drugs with more selective mechanisms of action. These new agents can target specific receptors and physiologic functions that more accurately focus in on the pathology of a particular disease process. Thus pharmacology is an ever-changing, growing body of knowledge that continually demands greater amounts of time and education from those in the health professions.
Organization The textbook is organized into 10 sections. The introductory section, General Concepts, presents the basic concepts and pharmacologic principles that apply to all drugs. Subsequent sections present the drug classes that pertain to a specific body organ system (nervous, cardiovascular, respiratory, etc.) or therapeutic indication (antihypertensives, infectious diseases, antineoplastics, etc.). The discussion of each drug classification concentrates on the mechanisms of action, main therapeutic effects, clinical indications, adverse reactions, and drug interactions.
Features Pharmacology: An Introduction hallmark features include: • Readability: Short readable chapters that link theory to practice. • Need-to-know Information: The content is focused on need-toknow information, so not to overload the learner. • Patient Administration and Monitoring Boxes provide the student with critical patient information and patient instructions regarding the drugs discussed in the chapter.
Other key features: • Learning Outcomes(LOs) The learning outcomes are correlated to the Revised Bloom’s Taxonomy and are numbered at the beginning of each chapter. Learning Outcomes are linked to the main chapter topic headings and the end-of-chapter review questions. This allows the student to more quickly associate the LOs with the location of that information in the text and with the answers to the review questions. • Notes to the Health Care Professional emphasizes important points and information for medical personnel involved in drug administration. • Drug tables organize and summarize the main pharmacologic features of the different drug classes, so students can review the key drugs at-a-glance. • New design with over 445 enhanced line art and photos that provide exciting and modern images showing the action of drugs and drug products. • Chapter reviews at the end of each chapter progress from simple to complex and provide immediate reinforcement of terminology and pharmacological concepts important for acquiring knowledge. Review exercises include: Multiple choice, labeling, sequencing, matching, classification, and documentation questions. These have been added to test the student’s ability to apply information presented in the chapter. The clinically relevant on-the-job questions allow students more opportunity to practice critical thinking skills.
What’s New? • New brilliant 4-color design that will draw the student’s attention to key features of the chapter. • 445 enhanced and new line art and photos bring content to life and engage the student to read further. • Revision and numbering of all learning outcomes to reflect the Revised Bloom’s Taxonomy guide the student on a clear path to mastering chapter content. • Correlation of learning outcomes to all major chapter headings and end-of-chapter review questions will help the student and instructor focus on key chapter content. • Addition of over 500 new end-of-chapter review questions and activities have been added to provide students with additional review opportunities that include multiple choice, multiple answer, labeling, sequencing, matching, classification, and documentation will challenge the student to test their knowledge of chapter concepts. • Drug Class at a Glance image, appearing at the beginning of each drug chapter, has been redesigned to represent a PDA (Personal Digital Assistant), commonly used by health professionals to verify drug information and dosages, summarizes the over-the-counter and prescription status, schedule of controlled drug status, FDA (Federal Drug Administration) pregnancy categories, and the main clinical indications for the drugs contained within that chapter. It provides a quick reference to the chapter drug information. • Over 140 revised tables organize and summarize the main pharmacologic features of the different drug classes. The tables list the generic drug name first followed by the trade name(s) which are italicized and put within parentheses.
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Updated drug information has been found by using several key sources: • US Federal Drug Administration (FDA) provides daily updates on drug approvals, drug safety issues, medication guides, and drug industry information. • FDA database on drug approvals and discontinuations is used to check status of market availability of branded and generic drugs. • HYPERLINK “http://www.centerwatch.com” www.centerwatch.com by Jobson Medical Information, LLC is a leading source of information about the clinical trials (pharmaceutical drugs and devices) industry. • HYPERLINK “http://www.factsandcomparisons.com” www.factsandcomparisons.com by Wolters Kluwer Health is a searchable database by drug name or therapeutic category for all FDA approved drugs. • National Library of Medicine and National Institutes of Health Medical provide information on conditions, diseases, wellness, over-the-counter (OTC) and prescription medication at different levels to facilitate understanding by professionals, students, patients, and consumers. • WebMD Health Professional Network provides evidence-based content, updated regularly by more than 8,000 attributed physician or health care provider authors and editors, and the latest practice guidelines in 38 clinical areas. It is reviewed by physicians at Harvard University Medical School. • Aetna InteliHealth provides credible information from trusted sources, including Harvard Medical School and Columbia University College of Dental Medicine. • Professional Organizations are dedicated to providing accurate information to patients and health care providers on a specific disease or condition.
• McGraw-Hill Connect Plus1 is a Web-based assignment and assessment platform that gives students the means to better connect with their coursework, with their instructors, and with the important concepts that they will need to know for success now and in the future. With Connect Plus1, instructors can deliver assignments, quizzes, and tests easily online. Students can practice important skills at their own pace and on their own schedule. With Connect Plus1, students also get 24/7 online access to an eBook—an online edition of the text—to aid them in successfully completing their work, wherever and whenever they choose.
• EZTest Test Bank containing over 900 multiple choice questions correlated to CAAHEP and ABHES competencies and tagged to chapter learning outcomes.
• McGraw-Hill LearnSmart: Pharmacology is a diagnostic learning system that determines the level of student knowledge, then feeds the student appropriate content. Students learn faster and study more efficiently. As a student works within the system, LearnSmart develops a personal learning path adapted to what the student has learned and retained. LearnSmart is also able to recommend additional study resources to help the student master topics. In addition to being an innovative, outstanding study tool, LearnSmart has features for instructors. There is a Course Gauge where the instructor can see exactly what students have accomplished as well as a built-in assessment tool for graded assignments. Students and instructors will be able to access LearnSmart anywhere via a web browser. And for students on the go, it will also be available through any iPhone or iPod Touch.
Teaching and Learning Supplements You will find many useful teaching and learning supplements with Pharmacology: An Introduction. These supplements create a complete package for today’s learners whether they are learning through distance education or in the typical classroom setting. • Online Learning Center (OLC), www.mhhe.com/hitner6e, includes the following instructor resources: • Instructor’s Manual featuring – lesson plans – lecture notes – discussion activities – answer keys – Internet connections that provide Web sites, directions, and suggestions that can be used to access additional information on diseases and the drugs used to treat them – additional readings from the literature that have been updated and provide clinically useful information regarding the use of drugs
• McGraw-Hill’s EZTest Test Generator, a flexible elec-
Pharmacology: An Introduction, contains: • 230 RMA and CMA style review questions correlated to CAAHEP and ABHES competencies • 140 dosage calculation problems • 230 NCLEX style review questions • 460 chapter quizzes • 23 animations with activities
• •
tronic testing program with over 900 test questions correlated to CAAHEP and ABHES standards that allows instructors to create tests from book-specific items. It accommodates a wide range of question types, and instructors may add their own questions. Multiple versions of the test can be created and any test can be exported for use with course management systems such as WebCT, BlackBoard, or PageOut. EZTest Online gives instructors a chance to easily administer EZTest-created exams and quizzes online. EZTest Online is available for Windows and Macintosh environments. PowerPoint® presentations include notes and key images Image bank featuring selected textbook images that can be utilized in classroom presentations, handouts, or questions
Preface
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Acknowledgments A sincere thanks to our reviewers who helped shape the direction of this book. Accuracy Reviewers Dorene Adams RN, MSN Solano Community College Hooshiyar Ahmadi, MD, DC Remington College Laura G. Barrow, BS Pharm., MS Pharm., J.D. Southwest Florida College Suzanne H. Carpenter, Ph.D., RN., C.N.E. Our Lady of The Lake College Pamela deCalesta, O.D. Linn-Benton Community College Linda Haider, RN, MSN, Assistant Professor, Nursing Minot State University Lynda T. Harkins, Ph.D., RRT McLennan Community College Michael T. Mockler, R.Ph., MBA Heald College Marilyn M. Turner, RN, CMA (AAMA) Ogeechee Technical College Damandeep S. Walia, MD The University of Kansas Medical Center Supplement Contributors Troy Andrew Cenac, MS, CPhT Brookhaven College Paula Lambert B.S., M.Ed., CPhT North Idaho College Pilar Perez-Jackson, CPhT Sanford Brown Institute Content Reviewers Diana Alagna, RN Branford Hall Career Institute John Albrecht Olympia College Glenn D. Appelt, Ph.D., R.Ph. Columbia Southern University Jane Barker, MS, RHIA, CMA Marshall University Mary Barko, CMA, MAEd/AEDL Ohio Institute of Health Careers Kevin D. Barnard, MS, CDEMTP, NREMTP, EMSI Cuyahoga Community College Tim Bloom Campbell University School of Pharmacy
Ilene Borze MS, RN Gateway Community College Deborah Briones, MSN Medical Careers Academy Jerry L. Bulen, D.O. Keiser University, Hillsborough Community College Dr. Beth Canfield-Simbro Mount Union College Troy Andrew Cenac, MS, CPhT Brookhaven College Kristin S. Coffman, RN, MSN Connors State College School of Nursing Leslie Z. Collier, RN, MSN/NE Brunswick Community College Roberta Connelley RN, BSN, MA Louisiana Technical College Laurie B. Cook, Ph.D. The College at Brockport, State University of New York Irene Coons MSN, RN, CNE College of Southern Nevada Carmen V. Cruz, MBA/HCM Anamarc College Brian Dickens MBA, RMA, CHI Keiser Career College James R. Dickerson Remington College Terry D. Edwards Remington College Richard Ray Espinosa, R.Ph., Pharm. D. Austin Community College Carla Lee Evans, RN Yorktown Business Institute Janet A. Evans, RN, MBA, MS, CCS, CPC-I Burlington County College Kimberly L. Fields, AAS RMA, CMA-AAMA, AHI Davis College Brenda Frerichs Colorado Technical University Paige S. Gebhardt, BA, RMT Sussex County Community College Sue K. Goebel, RN, MS, NP, SANE Mesa State College Stefanie Goodman MSN, RN, CMA (AAMA) Ivy Tech Community College Denise Gordon Solano Community College
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Margie Hair, RN, MSN Minot State University Lori Rae Hamilton RN, MSN Otero Junior College Catherine Harris RN, MSN Cape Cod Community College Julie Hart, RN, MSN Northern Kentucky University Robert M. Hawkes, MS, PA, NREMT-P Southern Maine Community College Terasa L. Hodges Independence Community College Charla K. Hollin, RN, BSN Rich Mountain Community College Jo Anne C. Jackson, EdD, RN Middle Georgia College Shelley Johnson, BBA, CPhT Griffin Technical College Patricia A. Kennedy, HM1USNR-RMA Centura College Joseph J. Krzanoski, Ph.D. University of South Florida College of Medicine Naomi Kupfer, CMA, CMBS Heritage College Richelle S. Laipply, Ph. D., MT(ASCP), CMA (AAMA) The University of Akron Paula Lambert BS, M.Ed., CPhT North Idaho College Anne P. LaVance, BS, CPhT Delgado Community College L.M. Liggan, M.Ed./PA/RMA/AHI-C National College Sarah M. Martin, Pharm.D., MBA Rogers State University Michelle C. McCranie Ogeechee Technical College D. P. Martinez, MD, MPH School of Allied Health, Florida Career College Michael Meir, MD HIT TCI College Laura Melendez, AA, BS, MA Keiser Career College Michael C. Melvin, R.Ph. Griffin Technical College Dr. William R Millington Albany College of Pharmacy, Union University Teresa Moore Albany Technical College Margaret L. Newton, MSN, RN St. Catharine College
Frances Nicholson, CPhT National College June Petillo, MBA, RMC Capital Community College Pilar Perez-Jackson, CPhT Sanford Brown Institute Stephen J. Poling, BAEd, CPhT Pima Medical Institute Mary M. Prorok, RN, MSN South Hills School of Business & Technology Cathy L. Pederson, Ph.D. Wittenberg University Mary M. Prorok, RN, MSN South Hills School of Business & Technology Kellie Rigdon Lockwood, RN, MSN East Central Technical College Shelly Schoonover RN, MS Connors State College School of Nursing Nena Scott, MDEd, RHIA, CCS, CCS-P Itawamba Community College Patricia Sell, MSEd National College Cathy Shallenberger, MS, PA-C Seton Hill University Betsy W. Skaggs, RN, BSN Ashland Community and Technical College Lynn-Dee Spencer, CPhT Hawaii Medical Institute Laura Spinelli RN BSN MSNEd Keiser Career College Laura Southard Durham, BS, CMA (AAMA) Forsyth Technical Community College Ron Swisher, Ph.D. Oregon Institute of Technology Irene May G. Tabay, BS. CPhT Heald College Sandi Tschritter, BA, CPhT Spokane Community College Jana W. Tucker, CMA/LRPT Salt Lake Community College Denise Way Lagueux Southeast Community College Georgann Weissman, DNP Keiser University Barbareta A. Welch McGill, RN, MSN, DRS North Carolina Central University Carolyn Sue Wright Coleman, LPN, AS National College
Acknowledgments
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What Every Student Needs to Know Many tools to help you learn have been integrated into your text.
Chapter Features Learning Outcomes present the key points you should focus on when reading the chapter. Consider this your road map to the knowledge and skills you will acquire upon studying this content.
Patient Administration and Monitoring summarizes important patient information and patient instructions about the drugs discussed in that chapter. It will expand your knowledge of medications and conditions.
Notes to the Health Care Professional emphasizes important points and information for medical personnel involved in drug administration.
Drug Tables organize and summarize the main pharmacologic features of the different drug classes. The tables list the generic drug name first followed by the trade name(s) which are italicized and put within parentheses. xxii
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Line Art and Photos provide a dynamic visual picture of the action of drugs and drug products to help you understand pharmacological processes that are discussed in the text.
Chapter Reviews provide immediate reinforcement of terminology and pharmacological concepts important for acquiring knowledge. Multiple-choice, matching, labeling, sequencing, and documentation questions have been added that challenge you to apply information presented in the chapter. The clinically relevant on-the-job questions allow you more opportunity to practice critical-thinking skills.
Appendices provide additional information pertinent to the study of pharmacology. You will find lists of abbreviations and symbols used in medical notations, weights and measures, and mathematical functions and terms. xxiii
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PART
1 G eneral C oncepts CHAPTER 1 Pharmacology: An Introduction 4
CHAPTER 2 Pharmacokinetics and Factors of Individual Variation 17
CHAPTER 3 Geriatric Pharmacology 36
CHAPTER 4 Math Review and Dosage Calculations
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Chapter 1
P harmacology: A n I ntroduction KEY TERMS adverse effect: general term for undesirable and potentially harmful drug effect. agonist: drug that binds to a receptor and activates a physiologic response or drug action. antagonist: drug that binds to a receptor and interferes with other drugs or substances from producing a drug effect. chemical name: name that defines the chemical composition of a drug. contraindications: situations or conditions when a certain drug should not be administered. controlled substance: drug that has the potential for abuse and thus is regulated by law. dose: a measurement of the amount of drug that is administered. drug: chemical substance that produces a change in body function. drug indications: intended or indicated uses for any drug. ED50: effective dose 50, or dose that will produce an effect that is half of the maximal response. generic name: nonproprietary name of a drug. LD50: lethal dose 50, or dose that will kill 50 percent of the laboratory animals tested. mechanism of action: explanation of how a drug produces its effects. nonprescription, over-the-counter (OTC) drug: drug that can be purchased without the services of a physician. pharmacology: study of drugs. potency: measure of the strength, or concentration, of a drug required to produce a specific effect. prescription drug: drug for which dispensing requires a written or phone order that can only be issued by or under the direction of a licensed physician. receptor: specific cellular structure that a drug binds to and that produces a physiologic effect. side effect: drug effect other than the therapeutic effect that is usually undesirable but not harmful. site of action: location within the body where a drug exerts its therapeutic effect, often a specific drug receptor. therapeutic effect: desired drug effect to alleviate some condition or symptom of disease. therapeutic index (TI): ratio of the LD50 to the ED50 in animal studies. toxic effect: undesirable drug effect that implies drug poisoning; can be very harmful or life-threatening. trade name: patented proprietary name of a drug sold by a specific drug manufacturer; also referred to as the brand name.
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Learning Outcomes
After studying this chapter, you should be able to 1.1 define pharmacology and its major subdivisions. 1.2 describe what a drug is and explain the differences between a therapeutic effect, side effect, and toxic effect. 1.3 explain the terms site of action, mechanism of action, receptor site, agonist, and antagonist.
1.4 explain the relationship between drug dosage and drug response, and the relationship between drug response and time. 1.5 recall the guidelines for drug safety and drug approval by the FDA. 1.6 identify drug nomenclature and the different terminology used in naming drugs. 1.7 recognize the drug references and understand the information they provide.
Introduction
Pharmacology is the study of drugs. A drug can be any substance that, when administered to living organisms, produces a change in function. Thus, substances such as water, metals (iron), or insecticides can be classified as drugs. However, the term drug commonly means any medication that is used for diagnosing, curing, or treating disease. Pharmacology is a subject that requires some background knowledge of anatomy, physiology, pathology, and related medical sciences. In that sense pharmacology is an integrative course of study that applies the relevant information of all medical sciences to the treatment of disease. Throughout this textbook the essential background information of anatomy, physiology, and pathology required for an understanding of drug action will be reviewed. Pharmacology is a large discipline that can be subdivided into different areas of study (Table 1:1). The major focus of Pharmacology: An Introduction is to provide an understanding of the mechanisms of action, main therapeutic effects, clinical uses, and adverse reactions of drugs. Completion of an introductory pharmacology course is only the beginning step in understanding this complex subject.
Table 1:1
Major Areas of Pharmacology Area
Description
Pharmacodynamics
Study of the action of drugs on living tissue
Pharmacokinetics
Study of the processes of drug absorption, distribution, metabolism, and excretion
Pharmacotherapeutics
Study of the use of drugs in treating disease
Pharmacy
Science of preparing and dispensing medicines
Posology
Study of the amount of drug that is required to produce therapeutic effects
Toxicology
Study of the harmful effects of drugs on living tissue
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LO 1.1
D RUG S OURCES A logical question to ask about pharmacology is “Where do drugs come from?” There are several sources of drugs. In the early days of medicine, most drugs were obtained from plant or animal sources. Plants and living organisms contain active substances that can be isolated, purified, and formulated into effective drug preparations. Examples of drugs derived from plants that are still widely used today include the analgesics morphine and codeine, which were obtained from the poppy plant (Papver somniferum); the heart drug digitalis, which was obtained from the purple foxglove (Digitalis purpurea); and the antimalarial drug quinine, which was obtained from the bark of the cinchona tree. Paclitaxel, an anticancer drug, is obtained from the yew tree. The search for new plant drugs is still very active. It is also interesting that many of the drugs of abuse such as cocaine, marijuana, mescaline, heroin, and others are derived from plants. Most of these drugs were used for hundreds of years by many different cultures in their religious and ritual ceremonies. Drugs obtained from living organisms include hormones such as insulin (from the pig) and growth hormone from pituitary glands. In addition, antibiotics such as cephalosporins and aminoglycosides have been derived from bacteria. The early history of pharmacology is filled with many interesting stories of discovery and medical experimentation. Textbooks devoted to the history of medicine and pharmacology are the best sources for additional information. Despite the many examples of drugs obtained from plants and living organisms, the main source of new drugs today is from chemical synthesis. Also, many of the drugs that once were obtained from plants and animals are now chemically synthesized in pharmaceutical laboratories. Advances in molecular biology and gene therapy have generated new types of drugs such as monoclonal antibodies. LO 1.2
T ERMINOLOGY R ELATED TO D RUG E FFECTS Another basic question that should be answered is “What actually is a drug? ” Every pure drug is a chemical compound with a specific chemical structure. Because of its structure, a drug has certain properties that are usually divided into chemical properties and biological properties. The properties of any drug determine what effects will be produced when the drug is administered. An important fact to remember is that, structurally, the human body is composed mostly of cells, even though these cells are highly organized into tissues, organs, and 6
systems. Consequently, drugs produce effects by influencing the function of cells. Pharmacologists know that all drugs produce more than one effect. Every drug produces its intended effect, or therapeutic effect, along with other effects. The therapeutic use(s) of any drug is referred to as the drug indication, meaning indications for use. The term contraindication refers to the situation or circumstance when a particular drug should not be used. Some drug effects, other than therapeutic effects, are described as undesirable. Undesired drug effects are categorized as side effects, adverse effects, and toxic effects.
Side Effects Many side effects are more of a nuisance than they are harmful. The dry mouth and sedation caused by some antihistamine drugs is an example. In many cases drug side effects must be tolerated in order to benefit from the therapeutic actions of the drug.
Adverse Effects Adverse effects are also undesired effects, but these are effects that may be harmful (persistent diarrhea, vomiting, or central nervous system [CNS] disturbances such as confusion) or that with prolonged treatment may cause conditions that affect the function of vital organs such as the liver or kidney. Reduction of dosage or switching to an alternative drug often will avoid or minimize these harmful consequences.
Toxic Effects Toxic effects, or toxicity, implies drug poisoning, the consequences of which can be extremely harmful and may be life-threatening. In these situations, the drug must be stopped and supportive treatment and the administration of antidotes may be required. The term most frequently used to describe the undesirable effects of drugs is adverse effects. However, you should be familiar with the other terms because they are used and, if used correctly, describe the nature and potential severity of undesired drug effects. Most drugs will cause all three types of undesired effects, depending on the dose administered. At low doses, side effects are common and often expected. At higher doses, additional adverse effects may appear. At very high doses, toxic effects may occur that can be fatal. Consequently, the undesired effects produced by most drugs are often a function of dosage, which is why a well-known physician from the Middle Ages, Paracelsus (1493–1541), made the famous statement, “only the dose separates a drug from a poison”—and we could add, “a therapeutic effect from a toxic effect.” Allied health
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personnel spend the majority of their time in patient contact. Therefore, they have an important responsibility to observe the undesired effects of drugs, to recognize the side effects that are often expected, and to identify and report the adverse and toxic effects that are potentially harmful and that often require medical attention. LO 1.3
BASIC C ONCEPTS IN P HARMACOLOGY As in any subject, fundamental principles and concepts form the basis upon which additional information can be added. Pharmacology is no exception, and the following basic concepts apply to any drug.
Site of Action The site of action of a drug is the location within the body where the drug exerts its therapeutic effect. The site of action of some drugs is not known; however, the site of action for most drugs has been determined. For example, the site of action of aspirin to reduce fever is in an area of the brain known as the hypothalamus. Within the hypothalamus the temperature-regulating center controls and maintains body temperature. Aspirin alters the activity of the hypothalamus so that body temperature is reduced. Throughout this book, when the site of drug action is known or suspected, it will be presented.
Mechanism of Action Mechanism of action explains how a drug produces its effects. For example, local anesthetic agents produce a loss of pain sensation by interrupting nerve conduction in sensory nerves. In order for nerve impulses to be conducted, sodium ions must pass through the nerve membrane. Local anesthetic agents attach to the nerve membrane and prevent the passage of sodium ions. Consequently, sensory nerve impulses for pain are not conducted to the pain centers in the brain. Knowledge of the mechanism of action of drugs is essential to understanding why drugs produce the effects that they do.
particular drug. Morphine, an analgesic drug, is an example of a drug that binds to a specific receptor. The receptors for morphine are located in the brain and are known as the morphine, or opioid, receptors. When morphine binds to its receptors, it produces cell changes that reduce the perception of pain. There are many different pharmacological receptors, and they will be described in the appropriate chapters.
Agonists and Antagonists Drugs that bind to specific receptors and produce a drug action are called agonists. Morphine is an example of an agonist. Drugs that bind to specific receptors and inhibit agonist drug action or cellular functions are called antagonists. Antagonists are also known as blocking drugs. Usually, antagonists bind to the receptors and prevent other drugs or body substances from producing an effect. Naloxone, a morphine antagonist, is administered to prevent, or antagonize, the effects of morphine in cases of morphine overdose. There are many examples in pharmacology where drug antagonists are used to prevent other substances from exerting an effect. When both agonist and antagonist drugs bind to the same receptor and are administered together, they compete with each other for the same receptor site. This effect is known as competitive antagonism. The amount of drug action produced depends on which drug (agonist or antagonist) occupies the greatest number of receptors. The actions of a drug agonist and antagonist are illustrated in Figure 1.1.There is also uncompetitive antagonism, which occurs when the antagonist drug interferes with the agonist drug action but not by binding to the same receptor. Figure 1.1 Competitive Antagonism at Work
Receptor Site Drug action is usually thought to begin after a drug has attached itself to some chemical structure located on the outer cell membrane or within the cell itself. For a few drugs and for some normal body substances, there seems to be a specific location on certain cells. This area is referred to as the receptor site. The attachment, or binding, of a drug to its receptors begins a series of cell changes referred to as the drug action. When a specific receptor site for a drug is known, that receptor site becomes the site of action for that
Receptor site on cell membrane
Agonist Antagonist Receptor site
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LO 1.4
DOSE-RESPONSE CURVE A fundamental principle of pharmacology is that the response to any drug depends on the amount of drug given. This principle is known as the dose-response relationship. A dose is the exact amount of a drug that is administered in order to produce a specific effect. The effect is referred to as the response. When the relationship between the dose and the response is plotted as a graph, it is referred to as a dose-response curve. Figure 1.2 illustrates the appearance of a typical dose-response curve for two similar drugs. The main feature of the dose-response relationship is that a drug response is proportional to the dose. As the dose increases, so does the magnitude of the response. Eventually, a maximal response is usually attained (100 percent response); further increases in dose do not produce any greater effect. This point on the graph is known as the ceiling effect. The ceiling effect reflects the limit of some drug classes to produce a particular effect. Above a certain dosage no further increase in effect is observed. Doses above those needed to produce the ceiling effect usually cause other undesired, often toxic, drug effects. Drugs within a drug class that are more potent than other drugs in the same class will produce the ceiling effect at a lower dosage, but they will not “raise the ceiling.” Drugs that continue to cause an increased effect as long as the dose is increased do not have a ceiling effect. A graded dose-response curve can be used to evaluate drug response among different drugs. In a graded dose-response curve, the increases in drug dosage are plotted against the increases in drug response. For
example, dose-response curves are used to compare the potency of similar drugs. Potency is a measure of the strength, or concentration, of a drug required to produce a specific effect. The dose that will produce an effect that is half of the maximal response is referred to as the effective dose 50, or ED50. The ED50 can be used to compare the potency of drugs that produce the same response. In Figure 1.2, the ED50 of drug A is 10 mg while the ED50 of drug B is 20 mg. Therefore, drug A is twice as potent as drug B. Twice the concentration of drug B is needed to produce the same response as drug A. Quantal (referred to as all-or-none) dose-response curves are used to show the percentage of a human or animal population that responds to a specific drug dosage. This information is important for determining the dosages that are recommended for various treatments. Quantal dose-response curves require an understanding of mathematical statistics that is beyond the scope of this textbook.
Time-Plasma Drug Concentration Curve The relationship of time and the plasma drug concentration is known as the time-plasma drug concentration curve. Duration of action is the length of time that a drug continues to produce its effect. Most individual drugs produce effects over a relatively constant period of time. Figure 1.3 illustrates the appearance of a typical timeplasma drug concentration curve. In this example, the
Figure 1.3 A Typical Time-Plasma Drug Concentration Curve Plasma drug concentration (mg/ml)
Figure 1.2 A Typical Dose-Response Curve
% Response
100
Ceiling effect
Drug A
Drug B
50
Toxic drug range Onset of action Termination of action
Duration of action Ineffective drug range 1
ED 50
5
8
10 15 20 Dosage of drug (mg/kg)
ED 50
25
Therapeutic drug range
2
3 4 Time in hours
5
This curve shows the change in plasma drug concentration over time in relation to onset, duration, and termination of drug action. Plasma drug concentrations that exceed the therapeutic range produce drug toxicity.
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plasma drug concentration is correlated with the onset, duration, and termination of drug action. After drug administration, a certain amount of time is required before a drug will produce an observable effect. The time from drug administration to the first observable effect is known as the onset of action. The drug response will continue as long as there is an effective concentration of the drug at the site of action. As the drug is metabolized and excreted, the response gradually decreases because the drug level is decreasing. When the plasma drug concentration falls below the therapeutic range, there is termination of drug action. Time-plasma drug concentration curves are used for predicting the frequency with which a drug must be administered in order to maintain an effective drug response. LO 1.5
D RUG S AFETY The federal Food and Drug Administration (FDA) has established guidelines that govern the approval and use of all drugs. Every drug must fulfill two major requirements before it can be approved for use in humans: efficacy (proof of effectiveness) and safety. The drug must be effective in the disease state for which it has been approved. Approved drugs must satisfy specific safety criteria as determined by extensive animal testing and controlled human testing. As discussed previously, the dose separates therapeutic effects from toxic effects.
Note to the Health Care Professional All drugs will act as poisons if taken in excess. Only the dose separates a therapeutic effect from a toxic effect. The goal of drug therapy is to select a dose that is in the therapeutic range and avoid doses that produce toxicity. This task is not easy because many factors influence the amount of drug that reaches its site of action. These factors—such as route of administration, absorption, and drug metabolism—will be discussed in Chapter 2, Pharmacokinetics and Factors of Individual Variation.
Drug safety receives much attention today. It is a constant source of concern and debate because the public is more aware of the dangers of drugs. In order to receive approval for use in humans, a drug must undergo several years of both animal and human testing and evaluation.
Several animal species must be used in order to evaluate the effectiveness and toxicity of a drug. One of the first tests that is performed is the lethal dose 50, or LD50. The LD50 is the dose that will kill 50 percent of the animals tested. The results of the LD50 and other tests are used to predict the safety of a drug.
Therapeutic Index The therapeutic index (TI) is a ratio of the LD50 to the ED50 of a drug. It gives an estimate of the relative safety of a drug. The equation is expressed as: TI = LD50/ED50 = 1000 mg/100 mg = 10
In this example, the therapeutic index is 10. This index indicates that ten times as much drug is needed to produce a lethal effect in 50 percent of the animals as is needed to produce the therapeutic effect in 50 percent of the animals. The therapeutic index is used only in animal studies to establish dosage levels for other testing procedures. The goal of drug therapy is to achieve therapeutic effects in all individuals without producing any harmful effects.
Adverse Drug Effects All drugs produce adverse and toxic effects if taken in excess. Most adverse effects are dose dependent, which means the higher the dose, the greater the chances for producing an adverse effect. Certain tissues are more frequently affected than others. Oral drugs often cause nausea, vomiting, and diarrhea because of gastrointestinal (GI) irritation. The liver, kidneys, brain, and cardiovascular system may be adversely affected because these organs are exposed to the highest concentrations of the drug. Drugs that produce birth defects, such as thalidomide, are known as teratogens. Drugs that promote the growth of cancerous tumors are called carcinogens. A few adverse effects are not dose dependent. These effects, such as drug idiosyncrasy and drug allergy, are determined by individual variation. Although all human beings are basically similar, there may be minor variations in certain enzymes or other body proteins. These variations may produce changes in drug metabolism that lead to unusual responses to a particular drug. An individual reaction to a drug with an unusual or unexpected response is known as an idiosyncrasy. Drug allergy occurs when an individual becomes sensitized to a particular drug (drug acts as an antigen) and produces antibodies against the drug. Subsequent administration of the drug leads to an antigen-antibody reaction. Antigen-antibody reactions involving drugs usually cause the release of histamine and other inflammatory Chapter 1 • Pharmacology: An Introduction
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mediators from cells known as mast cells. These inflammatory mediators produce the characteristic symptoms of allergy, which include rashes, hives, itching, nasal secretion, hypotension, and bronchoconstriction. In serious allergic reactions, the symptoms may be so severe that death may occur. The term anaphylaxis is used to describe these serious allergic reactions, which include severe hypotension, respiratory difficulties, and cardiovascular collapse. LO 1.6
D RUG N OMENCLATURE All drugs are chemicals, and many have long chemicalnames. As a result, all drugs are given a shorter name, known as the nonproprietary name, which is usually a contraction of the chemical name. The nonproprietary name is more commonly referred to as the generic name. When the drug is marketed by a pharmaceutical company, it is given a third name, known as the proprietary name, or trade name or brand name. Since several different pharmaceutical companies may market the same generic drug, there may be several different trade names for any one drug. Figure 1.4 gives three names of a commonly prescribed drug. Drugs are also divided into prescription and nonprescription drugs. Prescription drugs require a written or phone order (the prescription), which can only be issued by or under the direction of a licensed physician, dentist, or veterinarian. The prescription is a legal document that contains instructions for the pharmacist, who is licensed to dispense prescription medications. Nonprescription drugs, usually referred to as “over-the-counter” (OTC) drugs (such as aspirin, antacids, cold remedies), can be purchased anywhere and do not require the services of a physician or pharmacist. Figure 1.4 Drug Nomenclature
O
H
O
N
C
C
C2H5 C
N
C
H
O
C6H5
Chemical name: 5,5,-Phenylethylbarbituric acid Nonproprietary name: Phenobarbital (generic name) Proprietary name: Luminal (trade or brand name)
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LO 1.7
DRUG REFERENCES Medical libraries, hospital libraries, and educational institutions that provide medical education generally stock one or more drug reference books that provide drug information. The United States Pharmacopeia/National Formulary (USP/NF) is the official drug list recognized by the U.S. government. It provides information concerning the physical and chemical properties of drugs. The USP/NF is revised every five years and is used primarily by drug manufacturers to ensure drug production according to official government standards. The Physicians’ Desk Reference (PDR®) is the reference most widely used by physicians, pharmacists, and nurses for information relating to the use of drugs in the practice of medicine. It is updated yearly and provides information on indications for use, dosage and administration, contraindications, and adverse reactions. You should learn how to look up drugs in the PDR®. The PDR® is divided into sections, which are colorcoded. However, the section colors change from year to year so it is best to have a general understanding of the major sections. The main sections and their descriptions are listed below. Section 1: Manufacturers Index—Lists the pharmaceutical manufacturers, addresses, phone numbers, and emergency contacts as listed in the PDR®. Section 2: Brand and Generic Name Index—Gives the page number of each product by trade (brand) name and generic name. Section 3: Product Category Index—Lists all fully described products by prescribing category. Also includes information concerning controlled substances and FDA pregnancy categories. Section 4: Product Identification Guide—Presents full-color, actual-size photos of tablets, capsules, and dosage forms. Arranged alphabetically by company. Section 5: Product Information—Main section of book; describes pharmacology and clinical information concerning the use of these drugs. Arranged alphabetically by drug manufacturer. Drug Facts and Comparisons (F&C) is a loose-leaf index and drug information service subscribed to by most medical libraries. Drug information and new drug additions are updated monthly. This index provides the most current drug information on a regular basis. The United States Pharmacopeial Convention, Inc., publishes a series of volumes under the general title of
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United States Pharmacopeia Dispensing Information (USP DI) that are updated yearly. Volume I—Drug Information for the Health Care Professional—provides in-depth information about prescription and over-the-counter medications, and nutritional supplements. Volume II—Advice for the Patient—provides drug information for the patient. Drug Information—American Hospital Formulary Service provides detailed drug information. Drugs are organized according to therapeutic use and classification. It is updated yearly.
Drug Legislation Acts During the last century there was an increase in the discovery and introduction of new drugs. Correspondingly there was an increase in the reports of adverse drug effects and toxicities. Consequently, the government began to enact legislation aimed at ensuring the safety and effectiveness of drugs. The following is a brief summary of the major legislative acts. 1906: Federal Pure Food and Drug Act. This was the first real drug law that required drugs to have minimal standards of drug strength and purity. This law did not address the issue of drug efficacy or effectiveness. In 1912 the law was amended to include regulations for labeling and false claims of effectiveness. 1938: Federal Food Drug and Cosmetic Act. This act set standards for drug safety and was enacted after 40 patients died from taking an antibiotic that contained diethylene glycol as a solvent. Drug manufacturers now had to show proof of drug safety. 1962: Amendment to 1938 Federal Food Drug and Cosmetic Act. In 1960 thalidomide, a hypnotic drug, was discovered to produce phocomelia, a rare birth defect that caused abnormal limb development.
This act required pharmacological and toxicological research testing in several animal species before a drug could be tested in humans. The act also established the clinical requirements for human drug testing and, in addition, established the standards for both drug safety and effectiveness. This act is enforced by the Food and Drug Administration (FDA). 1970: Federal Comprehensive Drug Abuse Prevention and Control Act. This act, commonly referred to as the Controlled Substance Act, was amended in 1990. This act is designed to regulate the dispensing of drugs, called controlled substances, that have the potential for abuse. The controlled drugs are assigned to one of five schedules, depending on their medical usefulness and potential for abuse. This act is enforced by the Drug Enforcement Administration (DEA). Table 1:2 describes the schedules and provides examples of some controlled substances.
Chapter Openers In the chapters that deal with therapeutic drugs, a diagram will appear on the chapter opener page. The purpose of the diagram is to provide important information in a quick visual reference about the drugs included in that chapter. The information displayed informs the reader whether the drugs are available over-the-counter (OTC), by prescription, or a combination of both. In addition, it identifies which FDA Pregnancy Category (see Chapter 2) has been designated for the use of these drugs during pregnancy. Finally, the general clinical indications for the chapter drugs are presented. In the event individual drugs differ from the main representative drugs, the exceptions will be identified on the diagram.
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Table 1:2
Drug Schedules Defined in the Federal Comprehensive Drug Abuse Prevention and Control Act Schedule
Definition
Controlled drugs
Schedule I
Drugs with high abuse potential and no accepted medical use
Heroin, hallucinogens, marijuana; these drugs are not to be prescribed
Schedule II
Drugs with high abuse potential and accepted medical use
Narcotics (morphine and pure codeine), cocaine, amphetamines, short-acting barbiturates (Amobarbital, Secobarbital), nabilone; no refills without a new written prescription from the physician
Schedule III
Drugs with moderate abuse potential and accepted medical use
Moderate- and intermediate-acting barbiturates, dronabinol, anabolic steroids, preparations containing codeine plus another drug; prescription required, may be refilled five times in 6 months when authorized by the physician
Schedule IV
Drugs with low abuse potential and accepted medical use
Phenobarbital, chloral hydrate, zolpidem (Ambien), antianxiety drugs (Librium, Valium); prescription required, may be refilled five times in 6 months when authorized by the physician
Schedule V
Drugs with limited abuse potential and accepted medical use
Narcotic drugs used in limited quantities for antitussive (codeine) and antidiarrheal purposes (diphenoxylate, Lomotil ); drugs can be sold only by a registered pharmacist; buyer must be 18 years old and show identification. Some states require a prescription for schedule V drugs
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Chapter Review Understanding Terminology Match the definition in the left column with the appropriate term in the right column. (LO 1.1) ___ 1. The study of the amount of drug that is required to produce therapeutic effects.
a. pharmacodynamics
___ 2. The study of the harmful effects of drugs on living tissue.
c. pharmacology
___ 3. The study of the action of drugs on living tissue.
d. pharmacotherapeutics
___ 4. The study of drugs.
e. posology
___ 5. The science of preparing and dispensing medicines.
f. pharmacy
___ 6. The study of the processes of drug absorption, distribution, metabolism, and excretion.
g. toxicology
___
b. pharmacokinetics
7. The study of the use of drugs in treating disease.
Answer the following questions. 8. Define a drug. (LO 1.2) 9. Differentiate between therapeutic effect, side effect, and toxic effect. (LO 1.2) 10. What is the difference between site of action and mechanism of action? (LO 1.3) 11. What is the relationship between ED50, LD50, and therapeutic index? (LO 1.5) 12. Explain the difference between a prescription drug, OTC drug, and a controlled substance. (LO 1.6) 13. Explain the difference between idiosyncrasy and drug allergy. (LO 1.5) 14. Write a short paragraph describing the terms receptor site, binding, drug action, agonist, antagonist, and competitive antagonism. (LO 1.3)
Acquiring Knowledge Answer the following questions. 1. Examine a copy of the Physicians’ Desk Reference (PDR® ). Briefly describe the information found in Sections 1 through 5. (LO 1.7) 2. Look up the popular decongestant pseudoephedrine in Section 2 of the PDR®. What is your conclusion based on the available trade names? (LO 1.7) 3. What is a dose-response curve and what information is given by a dose-response curve? (LO 1.4) 4. What is the importance of a time-plasma drug concentration curve? How often would you estimate that a drug should be administered per day if the drug is eliminated in 4 hours? In 24 hours? (LO 1.4) 5. It is interesting that a drug can produce a therapeutic effect and an undesired side effect in one situation, and that the same side effect may be considered a therapeutic effect in another situation. Explain this phenomenon using the drug promethazine (Phenergan) as an example. (LO 1.2) 6. Obtain a copy of Drug Facts and Comparisons (F&C) from your school or library. It is divided into many sections. There are five sections that are frequently used. Examine each section and briefly explain how it might be useful in your field. (LO 1.7) a. Table of Contents b. Color Locator c. Color Locator Index d. Chapters; broken down by sections on drug classifications e. Index
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Chapter Review Continued Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. Obtain a copy of the PDR® from your school, nursing unit, or clinic and use it to do some sleuthing. Find the drugs that solve the following “medical mysteries.” (LO 1.7) a. Dan is currently taking the drugs Mephyton, Biaxin, and Entex LA for his chronic celiac disease and acute sinusitis. He was just prescribed Coumadin for thrombosis, and it had no therapeutic effect. Dan’s doctor suspects it’s a case of drug antagonism. Which drug is Dan taking that is antagonistic with Coumadin? b. Mary’s grandfather just came home from the doctor with a prescription for Vaseretic and he has already forgotten why he is supposed to take it. Explain what this drug is, its indications, and the most common adverse effects. c. Bill’s young wife was just prescribed Vibra-Tabs for a respiratory infection. Bill asks you what this drug is and is it safe for his wife to take, since she may be pregnant. Is it safe? 2. Assume that your employer has asked you to help screen patients for potential prescription drug problems. Look up the following frequently prescribed prescription drugs in the PDR® and provide the information requested. (LO 1.7) a. Indocin: What would tip you off that a patient was showing adverse effects to the drug? b. Bicillin: Describe symptoms of a patient who is allergic to this drug. c. Depakote: For whom is this drug contraindicated? Use the F&C or the PDR® to answer the following questions. 3. a. A patient calls you and states that he has found a single loose tablet on the carpet. He needs you to identify it for him. He describes it as a small blue tablet with a heart cut out of the middle. There is writing on the tablet, but it is too small to read. What is this medication? (LO 1.7) b. A patient calls with a minor problem. While traveling, she got her medications mixed together. She needs to take her Cordarone tablet but isn’t sure which one it is. Could you please describe it to her? (LO 1.7) 4. a. A physician wants to know what glucose-elevating products are available and whether they require a prescription. Look under the hormone section and find these products. List the available products, strengths, forms, and status. (LO 1.7) b. A physician wants to know the available forms and strength of Imitrex. Using the index, look up the medication and list the available forms, strengths, and package sizes. (LO 1.7) 5. Sarah Roberts has liver damage due to a past history of alcohol abuse. She is also taking carbamazepine 400 mg TID. Can she safely take acetaminophen for her chronic headaches? (LO 1.7)
Multiple Choice Use your critical-thinking skills to answer the following questions. 1. The study of drug absorption, distribution, metabolism, and excretion is known as (LO 1.1) A. pharmacotherapeutics B. pharmacodynamics C. pharmacokinetics D. pharmacy 2. The medical situation when a particular drug should not be administered is referred to as (LO 1.2) A. side effect B. adverse effect C. drug allergy D. contraindication
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3. An unusual or unexpected drug reaction by an individual is known as (LO 1.5) A. toxic effect B. antagonism C. idiosyncrasy D. side effect 4. The proprietary drug name supplied by a pharmaceutical company is also referred to as the (LO 1.6) A. generic name B. over-the-counter name C. trade name D. chemical name 5. The time from drug administration to the first observable drug effect is known as the (LO 1.4) A. duration of action B. onset of action C. ceiling effect D. maximal response 6. A drug that has the potential for abuse and is regulated by the Drug Enforcement Agency is classified as a (LO 1.7) A. poison B. OTC drug C. prescription drug D. controlled substance
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Select the terms below that relate to drugs having a dangerous result on the body. (LO 1.2) A. posology B. toxicology C. adverse effects D. antagonism 2. A medication that does not require a physician’s service to obtain. (LO 1.6) A. trade B. nonproprietary C. nonprescription D. brand 3. Which of the following could be categorized as adverse reactions? (LO 1.5) A. idiosyncrasy B. allergy C. teratogenicity D. carcinogenicity 4. Which term(s) could be associated with an agonist? (LO 1.3) A. receptor site B. toxicology C. blocking drug D. site of action 5. The time a drug continues to produce its effect. (LO 1.4) A. ED50 B. maximal response C. ceiling effect D. onset of action Chapter 1 • Chapter Review
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Chapter Review Continued Sequencing 1. Place the following in order of most beneficial to most harmful. (LO 1.2)
________________
________________
________________
Beneficial
________________ Harmful
adverse effect therapeutic effect side effect toxic effect
Classification 1. Place the following drugs into the correct controlled substance classification. (LO 1.5) Amphetamines
Narcotic antidiarrheals
Hallucinogens
Narcotic antitussives
Heroin
Anabolic steroids
Phenobarbital
Valium
Dronabinol
Short-acting barbiturates
Chloral hydrate
Lomotil
Marijuana
Morphine
Intermediate-acting barbiturates
Schedule I
Schedule II
Schedule III
Schedule IV
Schedule V
Labeling
Plasma drug concentration (mg/ml)
Fill in the missing labels. (LO 1.4)
0
1
2
3 4 Time in hours
5
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Chapter 2
Pharmacokinetics and Factors of Individual Variation KEY TERMS bioavailability: percentage of the drug dosage that is absorbed. drug absorption: entrance of a drug into the bloodstream from its site of administration. drug addiction: condition of drug abuse and drug dependence that is characterized by compulsive drug behavior. drug dependence: condition of reliance on the use of a particular drug, characterized as physical and/ or psychological dependence. drug distribution: passage of a drug from the blood to the tissues and organs of the body. drug excretion: elimination of the drug from the body. drug metabolism: the enzymatic biotransformation of a drug into metabolites. drug microsomal metabolizing system (DMMS): group of enzymes located primarily in the liver that function to metabolize (biotransformation) drugs. drug tolerance: decreased drug effect occurring after repeated drug administration. enzyme induction: increase in the amount of drug-metabolizing enzymes after repeated administration of certain drugs. enzyme inhibition: inhibition of drug-metabolizing enzymes by certain drugs. first-pass metabolism: drug metabolism that occurs in the intestines and liver during oral absorption of drugs into the systemic circulation. half-life: time required for the body to reduce the amount of drug in the plasma by one-half. individual variation: difference in the effects of drugs and drug dosages from one person to another. intramuscular (IM) injection: route of drug administration; drug is injected into gluteal or deltoid muscles. intravenous (IV) injection: route of drug administration; drug is injected directly into a vein. loading dose: initial drug dose administered to rapidly achieve therapeutic drug concentrations. maintenance dose: dose administered to maintain drug blood levels in the therapeutic range. oral administration: route of drug administration by way of the mouth through swallowing. parenteral administration: route of drug administration that does not involve the gastrointestinal (GI) tract. pharmacokinetics: describes the processes of drug absorption, drug distribution, drug metabolism, and drug excretion.
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Learning Outcomes
After studying this chapter, you should be able to
LO 2.4 list several factors of individual variation that can alter drug response.
LO 2.1 list different forms of drug products and the routes by which they are administered.
LO 2.5 understand the drug factors that relate to pediatric drug administration.
LO 2.2 understand the pharmacokinetic factors that determine the absorption, distribution, metabolism, and excretion of drugs.
LO 2.6 define the different types of drug interaction. LO 2.7 explain the basic terminology of chronic drug administration and drug dependence.
LO 2.3 identify how half-life, blood drug level, and bioavailability relate to drug response.
Introduction
The familiar saying “No two people are exactly alike” applies well to the effects produced by drugs. An identical drug and dose may produce an intense response in one individual and no observable effect in another. The major reasons for this are differences in pharmacokinetics and various factors of individual variation that exist among the patient population. Pharmacokinetics is a study of the factors that determine drug absorption, drug distribution, drug metabolism, and drug excretion. Individual variation is caused by a number of physical and psychological factors, including differences in age, sex, weight, genetic variation, emotional state, patient expectations (placebo effect), and the presence of other disease conditions (pathology) or other drugs. The remainder of this chapter will describe what happens to a drug between its administration and its elimination from the body. The interplay among the various biological factors determines the actual drug response.
LO 2.1
D RUG F ORMS
Solid and Semisolid Preparations
Drugs are prepared in various forms for administration. The physical and chemical properties of a drug usually determine which form will be most effective. In addition to the drug, most drug products contain other ingredients that facilitate the administration and absorption of the drug. Drug preparations should always be taken exactly as prescribed. Some of the more common drug forms and preparations follow.
The solid type of preparation is most common. A number of different kinds for different purposes are available.
Powders Powders are drugs or drug extracts that are dried and ground into fine particles.
Aqueous Preparations
Tablets
Syrups are commonly used aqueous preparations. A syrup is a solution of water and sugar to which a drug is added. Addition of flavoring agents eliminates the bitter taste of many drugs.
Tablets are drug powders that have been compressed into a convenient form for swallowing. They usually disintegrate in the stomach more rapidly than most other solid preparations.
Alcoholic Preparations
Troches and Lozenges
Elixirs, spirits, tinctures, and fluid extracts are drugs dissolved in various concentrations of alcohol, usually in the range of 5 to 20 percent.
These flattened tablets are allowed to dissolve in the mouth. They are commonly used for colds and sore throats.
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Capsules Gelatin capsules are used to administer drug powders or liquids. Gelatin capsules dissolve in the stomach, thereby releasing the drug.
Delayed-Release Products These are usually tablets or capsules that are treated with special coatings so that various portions of the drug will dissolve at different rates. Delayed-release products usually contain the equivalent of two or three single-dose units. They are designed to produce drug effects over an extended time.
Enteric-Coated Products Some drugs are very irritating to the stomach. Also, the gastric juices of the stomach can inactivate certain drugs. In these cases, the drug tablet or capsule is coated with an acid-resistant substance that will dissolve only in the less acidic portions of the intestines. Enteric-coated products should be taken on an empty stomach with water, either 1 hour before or 2 hours after meals.
Suppositories These are drugs mixed with a substance (cacao butter) that will melt at body temperature. Suppositories are intended for insertion into the rectum, urethra, or vagina.
Ointments Ointments or salves are soft, oily substances (petrolatum or lanolin) containing a drug that is applied to the skin or, in the case of ophthalmic ointments, to the eye.
Transdermal Products Transdermal products are administered through a bandage or patch system. The drug is released from the bandage or patch and is then absorbed through the skin into the systemic circulation. This method provides a continuous source of the drug over 24 hours or more. Nitroglycerin, estrogen, and clonidine are drugs available in this form.
Parenteral Injection Parenteral injection involves the administration of drugs by needle and syringe. Different injection sites such as subcutaneous (SC), intramuscular (IM), intravenous (IV), and others provide different rates of drug absorption and onset of action. Parenteral injection requires the practice of sterile technique and various safety precautions.
LO 2.1
R OUTES OF A DMINISTRATION Oral Administration The most common routes of drug administration are oral (PO) and parenteral. Parenteral administration is any route that does not involve the GI tract, including inhalation, hypodermic injection, and topical application. However, when the term parenteral is used, most individuals think of administration by injection with a needle and syringe. The oral administration route is the safest and the most convenient method. Oral administration usually requires 30 to 60 minutes before significant absorption from the GI tract occurs; therefore, the onset of drug action is delayed. Although some drugs are irritating to the stomach and may cause nausea, heartburn, and vomiting, administration of such drugs with sufficient amounts of water or with meals minimizes gastric irritation. However, food also delays drug absorption and therefore delays the onset of drug action. Besides convenience, another advantage of oral administration is that drugs given orally can be removed (within the first few hours) by gastric lavage or induced vomiting. This procedure is often employed in drug overdose (sleeping pills) or accidental poisoning.
Parenteral Administration The most common routes of parenteral administration include intramuscular (IM) injection, intravenous (IV) injection, inhalation, and topical application. IM injections are usually delivered into the gluteal or deltoid muscles. Extreme caution should be observed with gluteal injections to avoid injury to the sciatic nerve. The onset of action with IM administration is relatively short, usually within several minutes. Intravenous (IV) injection is usually restricted to use in the hospital. IV injection offers the fastest means of drug absorption because the drug is delivered directly into the circulation; therefore, the onset of drug action is almost immediate. However, there is some degree of risk because the drug cannot be withdrawn once it has been injected. Dosage miscalculations resulting in overdose can produce serious, even fatal, consequences. Inhalation involves administration of drug through the nose or mouth and into the lungs during respiratory inspiration. This route is especially useful for the local administration of drugs into the respiratory tract. Topical application of creams and ointments is used for local effects in the skin and in certain conditions for systemic effects, as with nitroglycerin ointment for the treatment of angina pectoris.
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Several other routes of administration are used in specific situations. The most commonly used routes are listed in Table 2:1 with examples of their indications for use. Other routes will be presented in the appropriate chapters. LO 2.2
D RUG A BSORPTION Drug absorption refers to the entrance of a drug into the bloodstream. In order for absorption to occur, the drug must be dissolved in body fluids. With the exception of IV or intraarterial administration, drugs must pass
through membranes of the GI lining and blood vessels before they gain access to the blood. Cell membranes are composed of lipids and proteins, which form a semipermeable barrier. Cells have special transport mechanisms that allow various substances (including drugs) to pass through the cell membrane. These mechanisms include filtration, passive transport, and active transport. Most drugs pass through membranes by passive transport. An important principle in passive transport is that the concentration of drug on each side of the membrane differs. In
Table 2:1
Routes of Drug Administration Route
Approximate onset of action
Indications
Examples
Oral (PO)
30 to 60 minutes
Whenever possible, the safest and most convenient route
Most medications—aspirin, sedatives, hypnotics, antibiotics
Sublingual
Several minutes
When rapid effects are needed
Nitroglycerin in angina pectoris
Buccal
Several minutes
Convenient dosage form for certain drugs
Androgenic drugs
Rectal
15 to 30 minutes
When patient cannot take oral medications and parenteral is not indicated, also for local effects
Analgesics, laxatives
Transdermal
30 to 60 minutes
Convenient dosage form that provides continuous absorption and systemic effects over many hours
Nitroglycerin, estrogen
Subcutaneous (SC)
Several minutes
For drugs that are inactivated by the GI tract
Insulin
Intramuscular (IM)
Several minutes
For drugs that have poor oral absorption, when high blood levels are required, and when rapid effects are desired
Narcotic analgesics, antibiotics
Intravenous (IV)
Within 1 minute
In emergency situations, where immediate effects are required, also when medications are administered by infusion
IV fluids (dextrose), nutrient supplementation, antibiotics
Intraarterial
Within 1 minute
For local effects within an internal organ
Cancer drugs
Intrathecal
Several minutes
For local effects within the spinal cord
Spinal anesthesia with lidocaine
Inhalation
Within 1 minute
For local effects within the respiratory tract
Antiasthmatic medications such as epinephrine
Topical
Within 1 hour
For local effects on the skin, eye, or ear
Creams and ointments
Vaginal
15 to 30 minutes
For local effects
Creams, foams, and suppositories
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passive transport, drug molecules diffuse from an area of high concentration to an area of low concentration (law of diffusion).
Note to the Health Care Professional It is very important for nurses and other health personnel to always follow the physician’s orders and the established guidelines for the administration of drugs. One practical approach to drug administration is referred to as “the five rights.” This approach advocates that the person dispensing the drug make a mental checklist that emphasizes giving the right patient the right drug in the right dose by the right route at the right time. In addition, different disciplines have added more rights such as having the proper documentation and the right attitude on the part of the person administering the drug. This aspect is important for generating a positive attitude in the patient toward therapy and contributes to a positive placebo response on the part of patients.
For example, following oral administration, there is a large amount of drug in the GI tract and no drug in the blood. Consequently, the drug molecules have a natural tendency to diffuse from the GI tract into the blood. The speed or rate of drug absorption also depends on the chemical properties of the drug and other factors such as the presence of food or other drugs. The properties of the drug that most determine absorption are lipid (fat) solubility of the drug and the degree of drug ionization.
Lipid Solubility Cell membranes are composed of a significant amount of lipid material. In general, the more lipid soluble a drug is, the faster it will pass through a lipid substance like the cell membrane. With the exception of general anesthetics (highly lipid soluble), most drugs are primarily water soluble and only partially lipid soluble. Many watersoluble drugs are weak acids or bases that can form charged particles or ions (ionization) when dissolved in body fluids. The absorption of water-soluble drugs is mainly influenced by the degree of drug ionization.
Drug Ionization Most drugs exist in two forms, ionized and un-ionized. Like electrolytes (Na+ and Cl−), ionized drugs are charged molecules because their atomic structure has
lost or gained electrons. The molecules then become either positively or negatively charged. In general, ionized drug molecules do not readily cross cell membranes. The un-ionized (uncharged) form of the drug is required in order for absorption to occur. The first generalization is that acid drugs (aspirin) are mostly un-ionized when they are in an acidic fluid (gastric juice). Consequently, drug absorption is favored. Conversely, acid drugs are mostly ionized when they are in an alkaline fluid; therefore, absorption is not favored and occurs at a slower rate and to a lesser extent. The second generalization is that basic drugs (streptomycin, morphine) are mostly un-ionized when they are in an alkaline fluid (lower GI tract after rectal administration). Conversely, these drugs are mostly ionized when they are dissolved in an acidic fluid like the upper GI tract. This is the reason why morphine is usually administered parenterally. In the stomach (pH 1 to 3) and upper intestinal tract (pH 5 to 6), basic drugs like morphine are absorbed more slowly and to a lesser extent than acidic drugs because they are primarily in an ionized form. The acid and base nature of drugs may be useful in treating drug toxicity (overdose). Drugs are generally excreted by the kidneys in an ionized form. To increase drug excretion, the pH of the urine can be altered. For example, to increase the renal excretion of an acid drug (aspirin), the urine is alkalinized (pH > 7). In an alkaline urine, acidic drugs are mostly ionized and more rapidly excreted. In the same manner basic drugs are more rapidly excreted by acidifying the urine (pH < 7).
Drug Formulation Drugs must be in solution before being absorbed. Tablets and capsules require time for the dissolution to occur. For this reason, liquid medications are generally absorbed faster than the solid forms. Drug particles can be formulated into different sizes, such as crystals, micronized particles, or ultramicronized particles. The smaller the size of the drug particle, the faster the rate of dissolution and absorption. LO 2.2
DRUG DISTRIBUTION After a drug gains access to the blood, it is distributed to the various tissues and organs of the body. Several factors determine how much drug reaches any one organ or area of the body. The main factors are plasma protein binding, blood flow, and the presence of specific tissue barriers. Chapter 2 • Pharmacokinetics and Factors of Individual Variation
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Plasma Protein Binding Several different proteins (albumin and globulins) are in the plasma and form a circulating protein pool. These plasma proteins help regulate osmotic pressure (oncotic pressure) in the blood and transport many hormones and vitamins. In addition, many drugs are attracted to the plasma proteins, especially albumin. The result is that some drug molecules are bound to plasma proteins while some drug molecules are unbound (free in the circulation). Only the unbound or free drug molecules can exert a pharmacological effect. The ratio of the bound to unbound drug molecules varies with the drug used. Some drugs are highly bound (99 percent), while other drugs are not bound to any significant degree. Occasionally, there is competition between drugs or other plasma substances for the same plasma protein binding site. In this situation, one drug may displace another. The result is that the concentration of free drug of one of the drugs increases, and this concentration can lead to increased pharmacological and adverse effects similar to overdosage.
Blood Flow The various organs of the body receive different amounts of blood. Organs such as the liver, kidneys, and brain have the largest blood supply. Consequently, these organs are usually exposed to the largest amount of drug. Some tissues, such as adipose tissue, receive a relatively poor blood supply and, as a result, do not accumulate large amounts of drug. However, highly lipid-soluble drugs can enter adipose tissue easily, where they can accumulate and remain for an extended period of time.
Blood-Brain Barrier In the case of the brain, an additional consideration is the blood-brain barrier. This barrier is an additional lipid barrier that protects the brain by restricting the passage of electrolytes and other water-soluble substances. Since the brain is composed of a large amount of lipid (nerve membranes and myelin), lipid-soluble drugs pass readily into the brain. As a general rule, then, a drug must have a certain degree of lipid solubility if it is to penetrate this barrier and gain access to the brain.
they were administered. Other drugs, however, must be chemically altered before they can be excreted by the kidneys. Drug metabolism, also referred to as biotransformation, is the chemical alteration of drugs and foreign compounds in the body. The liver is the main organ involved in drug metabolism. Within the cells of the liver are a group of enzymes that specifically function to metabolize foreign (drug) substances. These enzymes are referred to as the drug microsomal metabolizing system (DMMS). The DMMS utilizes cytochrome P450 enzymes that are important in oxidation and reduction reactions that convert drugs into their metabolites. The main function of this system is to take lipid-soluble drugs and chemically alter them so that they become water-soluble compounds. Water-soluble compounds can be excreted by the kidneys. Lipid-soluble compounds are repeatedly reabsorbed into the blood. Although most drugs are inactivated by metabolism, a few are initially converted into pharmacologically active metabolites. An interesting phenomenon occurs with some drugs, especially the barbiturates and other sedativehypnotic drugs. When these drugs are taken repeatedly, they stimulate the drug microsomal metabolizing system. By stimulating this system, the drugs actually increase the amount of enzymes (cytochrome P450’s) in the system; this process is referred to as enzyme induction. With an increase in the amount of enzymes, there is a faster rate of drug metabolism. Consequently, the duration of drug action is decreased for all drugs metabolized by the microsomal enzymes. In addition, other drugs can inhibit the drug microsomal-metabolizing enzymes to cause enzyme inhibition. This action slows the metabolism of all other drugs metabolized by these enzymes. This will increase the duration and intensity of the drugs inhibited. Enzyme induction and enzyme inhibition are common causes of adverse drug interactions. After oral administration, all drugs are absorbed into the portal circulation, which transports the drugs to the liver before they are distributed throughout the body. Some drugs are metabolized significantly as they pass through the liver this first time. This effect is referred to as first-pass metabolism. It can significantly reduce bioavailability and the amount of active drug that reaches the general circulation.
LO 2.2
D RUG M ETABOLISM Whenever a drug or other foreign substance is taken into the body, the body attempts to eliminate it. This usually involves excretion by one of the normal excretory routes (renal, intestinal, or respiratory). Some drugs can be excreted in the same chemical form in which 22
LO 2.2
D RUG E XCRETION The common pathways of drug excretion are renal (urine), GI (feces), and respiratory (exhaled gases). Although the liver is the most important organ for drug
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metabolism, the kidneys are the most important organs for drug excretion.
Figure 2.1 Movement of Drug in the Body
Renal Excretion After the blood is filtered through the glomerulus of the kidneys, most of the filtered substances are eventually reabsorbed into the blood. The exceptions to this are the urinary waste products and anything else that is in a nonabsorbable form. In order for drug excretion to occur, the drug or drug metabolite must be water soluble and preferably in an ionized form. As mentioned, acid drugs are mostly ionized in alkaline urine and basic drugs are mostly ionized in an acid urine. In the case of barbiturate or aspirin overdose (acid drugs), alkalinization of the urine with sodium bicarbonate will hasten elimination of either drug in the urine.
Parenteral Oral Absorption into bloodstream
Distribution to body Excretion
GI Excretion After oral administration, a certain portion of drug (unabsorbed) passes through the GI tract and is excreted in the feces. The amount varies with the particular drug used. In addition, there is another pathway involving the intestinal tract, the enterohepatic pathway. Certain drugs (fat-soluble drugs) can enter the intestines by way of the biliary tract. After the drug is released into the intestines (in the bile), it may be absorbed from the intestines back into the blood again. This is referred to as the enterohepatic cycle. The duration of action of a few drugs is greatly prolonged because of this repeated cycling of the drug (liver → bile → intestines → blood → liver).
Respiratory Excretion The respiratory system does not usually play a significant role in drug excretion. However, some drugs are metabolized to products that can be exchanged from the blood into the respiratory tract. General anesthetic gases are not totally metabolized. These drugs are excreted primarily by the lungs.
Miscellaneous Some drugs and drug metabolites also can be detected in sweat, saliva, and milk (lactation). Infants can be exposed to significant amounts of certain drugs after nursing (see the Drug Exposure During Infant Nursing section). In summary, following drug administration, the processes of drug absorption and distribution predominate as the drug is absorbed into the bloodstream and distributed to the various tissues. Later, drug metabolism and excretion predominate as the drug is eliminated from the body. However, once some drug reaches the
Metabolism
Liver
GI tract
Kidney
Following absorption the drug is distributed to all the tissues of the body. The liver metabolizes the drug so that the metabolites can be excreted by the kidneys and GI tract.
bloodstream, it is distributed to the liver and kidneys, which then begin metabolism and excretion. Consequently, all of the pharmacokinetic processes occur simultaneously to varying degrees depending on the time since administration. Figure 2.1 illustrates the interrelationship of the pharmacokinetic processes. LO 2.3
H ALF -L IFE The half-life of a drug is the time required for the blood or plasma concentration of the drug to fall to half of its original level. For example, after two half-lives only 25 percent of the drug that was absorbed remains in the blood. Half-life is important in determining the frequency of drug administration. In order to maintain a continuous drug effect, the drug must be given at intervals that keep the plasma concentration above the minimal effective concentration. The major factors that determine half-life are the rates of drug metabolism and excretion. The half-life of any drug is relatively constant if the individual has normal rates of drug metabolism Chapter 2 • Pharmacokinetics and Factors of Individual Variation
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and excretion. It can be prolonged when liver or kidney disease is present. In these situations, the dose or the frequency of administration can be reduced. LO 2.3
B LOOD D RUG L EVELS The intensity of drug effect is mainly determined by the concentration of drug in the blood or plasma. The drug effect and the amount of drug in the plasma are determined by an interplay among all of the pharmacokinetic processes (absorption, distribution, metabolism, and excretion) and the pharmacodynamics (pharmacologic effects) of the drug (Figure 2.2). As a drug is absorbed and distributed, the liver and kidneys begin the processes of metabolism and excretion. As long as the drug concentration in the plasma is within the therapeutic range, the drug concentration at the site of action will be sufficient to produce the pharmacodynamic or pharmacologic effect. Drug monitoring, the periodic measurement of blood drug levels, is performed to ensure that the level of drug in the blood is within the therapeutic range. Drug levels below the therapeutic range will not produce the Figure 2.2
desired drug effect, while levels above the therapeutic range cause increased side effects and toxicity. This concept is illustrated in Figure 2.3. There are some drugs that require several dosages or several days or weeks to reach the desired drug effect. In some clinical situations, it may be necessary to reach therapeutic drug levels as rapidly as possible. In these cases, a loading dose may be administered. A loading dose is usually an initial higher dose of drug, often administered IV, to rapidly attain the therapeutic drug level and drug effects. Loading doses are usually followed by maintenance doses that are smaller and calculated to maintain the drug level within the therapeutic range. LO 2.3
B IOAVAILABILITY Bioavailability is the percentage of the dose of a drug that is actually absorbed into the bloodstream. Differences in drug formulation, route of administration, and factors that affect GI absorption can influence bioavailability. A particular drug may be manufactured by many different drug companies and sold under different trade
Illustration of the Relationship between the Pharmacokinetic and Pharmacodynamic Processes That Determine the Pharmacologic and Clinical Drug Response
Drug concentration in tissues
Dose of drug administered Distribution Absorption
Pharmacokinetics
Drug concentration in systemic circulation
Drug metabolized or excreted Elimination
Drug concentration at site of action
Pharmacologic effect Pharmacodynamics Clinical response Toxicity
24
Effectiveness
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Figure 2.3
Plasma drug concentration (mg/ml)
Illustration of the Therapeutic Drug Range Maximal therapeutic concentration Onset of action Termination of action
Therapeutic drug range
Duration of action
1
2
3 4 Time in hours
5
Minimal effective concentration required to observe drug effect
names. In these situations, the amount of drug may be the same in each product, but the product may be different because of particle size, binders, fillers, and tablet coating. These differences may alter bioavailability. There have been examples of this in the past. Now, however, the Food and Drug Administration (FDA) regulates and requires bioavailability testing. LO 2.4
FACTORS OF I NDIVIDUAL VARIATION Many factors affect individual variation. These factors include age, weight, sex, genetic variation, emotional state, placebo effect, the presence of disease, and patient compliance.
Age The effects of drugs in different age groups is of particular importance. Infants, children, and the elderly are generally more sensitive to the actions of drugs than are younger adults. Drug considerations during pregnancy on fetal development, during the infant nursing period, and in infants and children are discussed in the section Pharmacokinetic Considerations for Pediatrics. Drug considerations for the elderly are presented in Chapter 3, Geriatric Pharmacology.
Weight Most adult dosages are calculated for the average adult weight, 150 pounds between the ages of 16 and 65. Obviously, all adults are not 150 pounds. In small individuals (100 pounds), the dose may have to be reduced. In larger
individuals (200 to 300 pounds), the dose may have to be increased. However, this approach does not always hold true, since many other factors are involved.
Sex and Percent Body Fat Females possess a higher percentage of body fat and a lower percentage of body water than do males of equal weight. Consequently, females may experience a greater drug effect than do males because the drug is dissolved in a smaller volume of body fluid. Lipidsoluble drugs are more widely distributed and may produce longer durations of action in females than in males. This same concept also applies to the differences in body fat composition between members of the same sex.
Genetic Variation Individuals tend to inherit the proteins and enzyme patterns of their parents. There is significant genetic variation in some of the drug-metabolizing enzymes, so individual differences can occur. If the difference affects the rate of drug metabolism, there may be a difference in the effects produced by the drug. An enzyme may be missing, in which case drug metabolism is extremely slow. A slowed metabolic rate may result in increased and prolonged drug effects that can lead to serious consequences. Examples of genetic variation will be discussed in specific chapters.
Emotional State Differences in drug effects can be caused by the emotional state of the individual. For example, an individual who is excited or extremely anxious may require a larger dose of hypnotic or tranquilizer than an individual who is not emotionally stimulated but who still has difficulty sleeping.
Placebo Effect Patients come to physicians and hospitals with varying expectations. It has been observed that if patients have a positive attitude and think that the drug or treatment will help, chances are the patients claim an improvement whether there actually is one or not. In some studies, patients have been unknowingly given sugar pills or placebos instead of an actual drug. A large percentage of these patients claim an improved condition even though they received no real drug. Likewise, patients with hostile or negative attitudes, who feel that nothing will help their condition, usually say that they feel no difference or even worse after a specific treatment or medication. The influence of one’s mind on the course of treatment is referred to as the placebo Chapter 2 • Pharmacokinetics and Factors of Individual Variation
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effect. This phenomenon can be used by the medical and nursing staff to enhance the positive attitude of patients. Thus, the patients stand a better chance of responding successfully to therapy.
training must be given to ensure that all patients understand dosing instructions.
Presence of Disease
PHARMACOKINETIC CONSIDERATIONS FOR PEDIATRICS
The presence of other diseases that are debilitating or that decrease the function of some vital organ usually makes an individual more susceptible to the effects and adverse reactions of drug therapy. As mentioned, the liver and kidneys are especially important, since these two organs are exposed to the highest drug levels. For this reason, liver and kidney function are often adversely affected by drugs. Patients with hepatic or renal disease suffer a greater incidence of adverse drug effects because they are unable to eliminate the drug and its metabolites effectively. Consequently, plasma drug levels are much higher in these patients due to accumulation of the drug in the plasma.
Patient Compliance Drug compliance refers to taking a drug exactly as prescribed. If dosages are forgotten or skipped, the drug effects will be reduced or absent. This is referred to as noncompliance. Noncompliance is often a problem in geriatric patients who may have memory difficulties and who are easily confused by complicated dosing schedules, especially when several different drugs are involved. Particular care and sufficient patient instructions and
LO 2.5
Fetal Period During Pregnancy Before birth the developing fetus will be exposed to most drugs taken during pregnancy. The placenta is not a drug barrier, and drug absorption and distribution to the fetus follow the same principles as with other maternal organs (passive diffusion based on lipid solubility and ionization). Although there are relatively few drugs that have been proven to be teratogenic (cause birth defects), it is recommended that drug exposure during pregnancy should be avoided if possible. This is especially true during the first trimester when organogenesis, the formation of body organs, is occurring. Drugs that are teratogens may cause spontaneous abortion, growth retardation, birth defects, or carcinogenesis (development of cancer). The Food and Drug Administration has established guidelines, the FDA Pregnancy Categories (see Table 2:2), that classify drugs based on fetal risk. Table 2:3 lists some drugs that have been associated with teratogenicity in humans. Consult Section 6 in the PDR® for an expanded list of drugs assigned to the FDA Pregnancy Categories.
Table 2:2
Description of FDA Pregnancy Categories Category
Description
Pregnancy category A
Drug studies in pregnant women have not yet demonstrated risk to the fetus
Pregnancy category B
Drug studies have not been performed in pregnant women; animal studies have not demonstrated fetal risk
Pregnancy category C
Drug studies have not been performed in pregnant women or in animals, or animal studies have revealed some teratogenic potential but the risk to the fetus is unknown
Pregnancy category D
Drug studies have revealed adverse risk to the fetus. The benefit-to-risk ratio of the drug must be established before use during pregnancy
Pregnancy category X
Drug studies have revealed teratogenic effects in women and/or animals. Fetal risk clearly outweighs benefit. Drug is contraindicated in pregnancy
Pregnancy category NR
Drug has not yet been rated by FDA
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Table 2:3
Examples of Drugs with Demonstrated Teratogenic Risk in Humans Drug
Teratogenic effect
Androgens (male hormone)
Masculinization of female fetus
Carbamazepine
Craniofacial and fingernail deformities
Diethylstilbestrol
Vaginal tumors and genital malformations in offspring
Estrogen (female hormone)
Feminization of male fetus
Lithium
Cardiac defects
Phenytoin
Craniofacial and limb deformities, growth retardation
Retinoic acid
Craniofacial, cardiac, and *CNS defects
Thalidomide
Phocomelia (limb deformities)
Warfarin
Facial, cartilage, and CNS defects Abbreviations: *CNS, central nervous system
Drug Exposure During Infant Nursing Drugs administered to nursing mothers appear in breast milk to varying degrees. Unfortunately there is a lack of controlled studies and reliable information in this area. The major concern is that the drug concentration in the milk will be high enough to produce undesired or harmful effects in the infant. Generally, the recommendation is to avoid unnecessary drug administration. Usually the infant experiences the same pharmacological effects as in the mother. For example, laxatives may cause infant diarrhea, while sedatives and hypnotics will cause drowsiness and lethargy. Other drugs such as anticancer agents or drugs with increased toxicities are contraindicated unless the benefit to the mother clearly outweighs the risk to the infant. Table 2:4 lists some of the drugs that appear in breast milk.
beyond the obvious difference in body weight. These differences tend to decrease with advancing age, especially after the first year of life.
Drug Administration and Absorption Neonates and infants have a small skeletal muscle mass. In addition, limited physical activity results in a lower blood flow to muscle. Therefore, absorption after IM injections is slower and more variable. There is also increased risk of muscle and nerve damage with IM injections. In serious situations the IV route is more reliable and generally preferred. The skin of neonates and infants is thinner and topically applied drugs are more rapidly and completely absorbed into the systemic circulation. With regard to oral administration, the gastric pH of premature babies and neonates is less acidic. This could result in decreased bioavailability and lower blood levels of orally administered drugs that are acidic in nature.
Pediatric Considerations
Drug Distribution
There are a number of pharmacokinetic and pharmacodynamic differences between pediatric and adult patients. Neonates (0 to 1 month), infants (1 to 12 months), and children of increasing age are not simply “small adults.” There are a number of factors that must be considered that generally require reduction in dosage
Pediatric patients possess a higher percentage of body water and a lower percentage of body fat. These differences decrease the distribution of lipid-soluble drugs to body tissues and organs. This tends to cause higher drug blood levels. Water-soluble drug distribution is increased (greater peripheral drug distribution), which Chapter 2 • Pharmacokinetics and Factors of Individual Variation
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Table 2:4
Examples of Drugs That Cross into Breast Milk Following Maternal Use Drug class
Examples
Antibiotics
Ampicillin, erythromycin, penicillin, streptomycin, sulfa drugs, tetracyclines
Antiepileptic agents
Phenytoin, primidone
Antithyroid agents
Thiouracil
CNS stimulants
Nicotine
Laxatives
Cascara, danthron
Narcotic analgesics
Codeine, heroin, methadone, morphine
Nonnarcotic antiinflammatory agents
Phenylbutazone
Sedative-hypnotic agents
Barbiturates, chloral hydrate
Tranquilizers (antipsychotic agents)
Chlorpromazine, lithium
tends to lower drug blood levels. These effects are all in comparison to the adult effects. While pediatric patients have higher percentages of water, they are more easily dehydrated by vomiting and diarrhea. The resulting reduction of body fluids will increase drug concentrations and drug effects. Plasma protein levels are also lower, especially in neonates. This results in lower plasma protein binding of drugs and, therefore, greater amounts of unbound or “free” drug. Since only the unbound drug exerts an effect, there will be a greater intensity of drug effect.
Drug Metabolism and Excretion There is a reduced capacity for drug metabolism and drug excretion during the first several years of life. Consequently, drug elimination occurs more slowly and the duration of drug action is prolonged. The decreases in drug metabolism and excretion are most evident in the neonate and infant. After the first year, drug metabolism and excretion gradually become proportional to those of the adult.
Dosage Adjustment Dosage calculations in pediatrics are based mainly on age, body surface area, and body weight. The rules and formulas used for these calculations are presented in Chapter 4, Math Review and Dosage Calculations. 28
LO 2.6
D RUG I NTERACTIONS Drug interaction refers to the effects that occur when the actions of one drug are affected by another drug. There are many different types of drug interactions. Some drugs interfere with each other during GI absorption and therefore should not be administered at the same time. Other drugs may interfere with plasma protein binding, drug metabolism, or drug excretion. Throughout this book, the common drug interactions will be given. Table 2:5 explains the general terms that are associated with drug interactions. LO 2.7
T ERMINOLOGY A SSOCIATED W ITH C HRONIC D RUG U SE AND A BUSE The chronic use of certain drugs results in a number of physiologic and pharmacologic changes in drug response. Drug tolerance and drug dependence are two important phenomena involved in chronic drug use.
Tolerance Drug tolerance is defined as a decreased drug effect that occurs after repeated administration. In order
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Table 2:5
Terminology of Common Drug Interactions Term
Explanation
Incompatibility
Usually refers to physical alterations of drugs that occur before administration when different drugs are mixed in the same syringe or other container
Additive effects
When the combined effect of two drugs, each producing the same biological response by the same mechanism of action, is equal to the sum of their individual effects
Summation
When the combined effect of two drugs, each producing the same biological response but by a different mechanism of action, is equal to the sum of their individual effects
Synergism
When the combined effect of two drugs is greater than the sum of their individual effects
Antagonism
When the combined effect of two drugs is less than the sum of their individual effects
to attain the previous drug effect, the dosage must be increased. This is a common occurrence in individuals who abuse drugs such as cocaine, barbiturates, morphine, and heroin. There is also the phenomenon of crosstolerance, which is the tolerance that exists between drugs of the same class. Tolerance is caused by changes or adaptations that occur in response to repeated drug exposure. The main types of tolerance are referred to as metabolic tolerance and pharmacodynamic tolerance. Metabolic tolerance is caused by enzyme induction—the drug increases the drug-metabolizing enzymes (DMMS) and the dose must be increased in order to attain the same previous effect. Pharmacodynamic tolerance is caused by the ability of some drugs to decrease the number of drug receptors. This usually takes several weeks or months and is referred to as “down-regulation.” With the reduction in drug receptors there is a reduction in intensity of drug effect.
Drug Dependence Drug dependence is a condition wherein reliance on the administration of a particular drug becomes extremely important to the well-being of an individual. Drug dependence is usually characterized as psychological and/or physical. When the drug is used repeatedly
for nonmedical purposes, the term drug abuse is applied. Any activity that is repeated and that provides pleasure involves a psychological component of behavior. The smoking of tobacco, for example, is an activity associated with psychological dependence. Deprivation of smoking causes some unpleasant feelings, but does not result in serious medical consequences. All drugs that are abused have varying degrees of psychological dependence associated with them. Many abused drugs also produce physical dependence when taken for prolonged periods of time and usually at increasing dosages. Deprivation of these drugs leads to a physical withdrawal syndrome that is very unpleasant, characterized by measurable changes in many bodily functions, and that may cause serious medical consequences. The withdrawal reactions from alcohol, barbiturates, and opiate drugs are examples of this type of reaction. When drug dependence is particularly severe and compulsive drug behavior dominates all other activities, the term drug addiction is used. Information concerning tolerance and dependence of specific drug classes can be found in Chapters 12 (Sedative-Hypnotic Drugs and Alcohol), 13 (Antipsychotic and Antianxiety Drugs), 15 (Psychotomimetic Drugs of Abuse), and 19 (Opioid Analgesics).
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Chapter Review Understanding Terminology Match the description in the left column with the appropriate term in the right column. (LO 2.6, LO 2.7) ___ 1. When the combined effect of two drugs, each producing the same biological response by the same mechanism of action, is equal to the sum of their individual effects. ___ 2. When the combined effect of two drugs, each producing the same biological response but by a different mechanism of action, is equal to the sum of their individual effects. ___ 3. When the combined effect of two drugs is greater than the sum of their individual effects.
a. additive effects b. antagonism c. incompatibility d. summation e. synergism f. tolerance
___ 4. When the combined effect of two drugs is less than the sum of their individual effects. ___ 5. Usually refers to physical alterations of drugs that occur before administration when different drugs are mixed in the same syringe or other container. ___ 6. Decreased drug effects after chronic administration.
Answer the following questions in the spaces provided. 7. Differentiate between the following terms: parenteral administration, oral administration, intramuscular injection, and intravenous injection. (LO 2.1) 8. What is the main disadvantage to the IV method of drug administration? (LO 2.1) 9. By what method of cell transport are most drugs absorbed? What are the main requirements for drug absorption? (LO 2.2) 10. Explain why alkalinization of the urine increases the rate of excretion of drugs such as aspirin or phenobarbital. (LO 2.2) 11. Briefly describe the main factors that determine drug distribution. (LO 2.2) 12. What is the major requirement for a drug if it is to gain access to the brain? (LO 2.2) 13. What is the drug microsomal metabolizing system, and what is its main function? (LO 2.2) 14. List the major pathways of drug excretion. (LO 2.2) 15. Why is the plasma drug concentration important? What are the main factors that determine plasma concentration? (LO 2.3) 16. List the factors that can contribute to individual variation in drug response. (LO 2.4)
Acquiring Knowledge Answer the following questions. 1. A single IV injection of 100 mg of a drug with a half-life of 4 hours is administered to a young adult. Approximately how many hours will it take to totally eliminate this dosage from the body? (LO 2.3) 2. A drug has a bioavailability of 70 percent after oral administration. How many milligrams of drug will be absorbed following a dosage of 200 mg? What would be the expected effect on bioavailability if a large meal was ingested just before administration? (LO 2.3) 3. Your grandmother has just been prescribed a very lipid-soluble drug. Would you expect her dosage to be larger or smaller than that for a younger adult? Explain. (LO 2.5)
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4. Rifampin is a drug that causes enzyme induction. Would you have to increase or decrease the dosage of another drug taken concurrently if it required drug metabolism for elimination? What change in dosage would a very water-soluble drug require? (LO 2.2) 5. Individuals who become dependent on drugs such as alcohol or narcotics require a steady supply of drug for administration or they will experience unpleasant and potentially harmful effects. Individuals with diabetes require insulin injections on a daily basis or they will experience potentially harmful effects. Are the individuals taking insulin dependent on the drug? Is there a difference between the dependence on insulin versus alcohol? Explain. (LO 2.7)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. Assume that your new job in a neighborhood health clinic is to identify individual patient factors that might affect the bioavailability of drugs prescribed for the patients. Following are descriptions of five of the clinic’s patients whom you dealt with this morning. For each patient, identify one factor that could affect drug bioavailability and explain how drug dosage could be changed to compensate for it. a. Jonathan is a 35-year-old male with a medical history of stomach complaints but no evidence of ulcer. When Jonathan visited the clinic this morning he weighed in at 324 pounds. He presented with upper respiratory symptoms attributable to allergy and was prescribed a decongestant and an antihistamine. (LO 2.3) Factor Dosage change b. Lisa is a 25-year-old female weighing 103 pounds. She is in good health. At her clinic visit this morning, she complained of muscle pain caused by moving furniture into her new apartment. She was prescribed a muscle relaxant and a pain reliever. (LO 2.3) Factor Dosage change c. Al is a 50-year-old male alcoholic weighing 150 pounds. His history reveals long-term alcohol abuse. Liver function tests run last month showed some enzyme abnormalities. Al’s visit to the clinic this morning was for a sinus infection. He was prescribed an antibiotic and a decongestant. (LO 2.3) Factor Dosage change d. Janet is a 49-year-old weighing 130 pounds. Her visit to the clinic this morning was for insomnia, which she has suffered since her husband’s death 2 weeks ago. It was clear from her behavior at the clinic today that she’s emotionally distraught. She was prescribed a mild sedative. (LO 2.3) Factor Dosage change e. Jessie is a 5-year-old girl weighing 43 pounds. She presented at the clinic this morning with an upper respiratory virus and strep throat. She was prescribed an antibiotic for the strep throat and pediatric ibuprofen for fever and discomfort. (LO 2.3) Factor Dosage change 2. Assume that you have volunteered to work a nonprescription drug hotline. Your job is to give people who call assistance with over-the-counter drugs. How would you react—and why—to the following anonymous callers? a. Caller A is worried about taking too much aspirin. She didn’t realize until after she took the capsules that they were double the dose of the product she usually takes. She wants to know if there’s something she might have on hand at home that she could take to counter the effects of the extra aspirin in her system. (LO 2.2) b. Caller B wants to know if it’s all right to take a laxative while she is breast-feeding her baby. (LO 2.5) Chapter 2 • Chapter Review
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Chapter Review Continued Multiple Choice Questions Use your critical-thinking skills to answer the following questions. 1. The drug administration route demonstrating the slowest onset of action is (LO 2.1) A. inhalation B. transdermal C. intramuscular D. sublingual 2. In order for drugs to cross the blood-brain barrier, they must be (LO 2.2) A. ionized B. positively charged C. water soluble D. lipid soluble 3. First-pass metabolism refers to the metabolism of drugs in the (LO 2.2) A. kidney B. blood vessels C. liver D. heart 4. Drug X has a half-life of 6 hours. How much drug is left in the body 18 hours after an IV injection of 1200 milligrams (mg) (LO 2.3) A. 75 mg B. 150 mg C. 300 mg D. 600 mg 5. Drugs that have demonstrated teratogenic effects in women are classified as Pregnancy Category (LO 2.5) A. B B. C C. D D. X 6. When a drug increases the rate of drug metabolism of other drugs, the process is termed (LO 2.2) A. first-pass metabolism B. enzyme induction C. enzyme inhibition D. enterohepatic cycling
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Drug absorption is affected by which of the following? (LO 2.2) A. drug ionization B. blood flow C. formulation D. half-life 2. Which factors of individual variation are dependent upon the patient’s attitude toward treatment? (LO 2.4) A. weight B. age C. genetic variation D. placebo effect
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3. Harm to a fetus has been demonstrated in which pregnancy categories? (LO 2.5) A. Category A B. Category B C. Category C D. Category D 4. Which types of drug interactions show a combined effect equal to the sum of the individual effects of two drugs? (LO 2.6) A. summation B. synergism C. antagonism D. incompatibility 5. Factors that affect bioavailability include which of the following? (LO 2.3) A. drug formulation B. route of administration C. GI absorption D. half-life
Sequencing 1. Place the following in order of quickest onset of action to slowest onset of action. (LO 2.1)
________________
________________
________________
Quickest
________________ Slowest
Oral Sublingual Rectal Intravenous
Classification 1. Put the following drug forms into their appropriate type of preparation. (LO 2.1) Spirits
Capsules
Tinctures
Syrups
Fluid extracts
Injectable
Ointments
Powders
Alcoholic Preparations
Solid or Semisolid Preparations
Aqueous Preparations
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Chapter Review Continued Document Exercise Based on the following drug labels, indicate the route of administration for each. (LO 2.1)
1. _____________
2. _____________
3. _____________
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4. _____________
5. _____________
Labeling
Parenteral
1. Fill in the missing labels. (LO 2.2)
Oral
Distribution to body
GI tract
Liver
Kidney
For interactive animations, videos, and assessment visit:
www.mcgrawhillconnect.com Chapter 2 • Chapter Review
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Chapter 3
G eriatric P harmacology KEY TERMS creatinine: a metabolite of muscle metabolism that is excreted in the urine in proportion to renal function. creatinine clearance: a measure of renal creatinine excretion that is used to evaluate renal function. drug compliance: following drug prescription directions exactly as written. enterohepatic recycling: the process whereby drug is eliminated from the liver/biliary tract into the Gl tract and then reabsorbed from the Gl tract back to the liver. geriatrics: medical specialty that deals with individuals over 65 years of age. mixed-function oxidase system: drug microsomal metabolizing enzymes (DMMS) that decrease with age and slow the rate of drug oxidation and metabolism. polypharmacy: the situation in patients whose treatment involves multiple drug prescriptions.
Learning Outcomes
After studying this chapter you should be able to 3.1 describe the main physiological changes that occur with aging. 3.2 list several factors that affect the absorption and distribution of drugs in the elderly.
3.4 recognize the effects of nutrition and age-related diseases on drug response. 3.5 explain the problems associated with drug compliance in the elderly.
3.3 list several factors that affect the metabolism and excretion of drugs in the elderly.
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Introduction LO 3.1
The process of aging begins slowly in the young adult and proceeds at varying individual rates throughout life. The effects of genetics, nutrition, exercise, injury, disease, environment, and many other factors affect the rate of aging. Regardless of the factors that can influence the aging process, there are predictable changes that occur in every individual with the passing of time. This chapter will focus on the age-related changes that influence drug response. The term geriatric refers to individuals over 65 years of age. Geriatric medicine, the medical treatment of the elderly, has developed into a medical specialty.
LO 3.3
D RUG U SE IN THE E LDERLY The number of older individuals in the population is increasing and will continue to increase in the future. The dramatic increase in life expectancy over the past few decades has been a significant factor in the growth of this population. The progress of medical technology, including the discovery and development of many new and more effective drugs, has played an important role in improving health and quality of life, in addition to increasing the number of years a person can live. The cost and social impact of new and often expensive treatments also have raised a number of moral and ethical issues concerning the prolongation of life at any cost. Compared to other age groups, the geriatric population accounts for the highest percentage of drug prescriptions per year. Drug use increases with increasing age, and the number of drugs consumed in the geriatric population averages between three and four drugs per individual. Both the nature and frequency of adverse drug reactions increase with age. It is not uncommon for elderly patients with multiple diseases such as hypertension, arthritis, chronic obstructive pulmonary disease, and heart failure to have prescriptions for 10 or more drugs. The number of possible adverse reactions and drug-drug interactions with this number of drugs is almost beyond calculation.
Physiological Effects of Aging on Pharmacokinetic Processes Aging is a continuous process that begins when life is conceived. However, most healthy individuals do not begin, or will not admit to, feeling the effects of age until the third or fourth decade. It has been estimated that after 25 or 30 years of age, the cardiac output, the amount of blood pumped by the heart per minute, decreases by
approximately 1 percent per year. This means that by the age of 65, the liver and kidneys, for example, are receiving significantly less blood per minute than they did 40 years ago at age 25. This, in particular, can have important consequences for drug action and the ability of the body to eliminate drugs. In addition, the size of most body organs decreases with age and, therefore, there are fewer cells to carry out organ functions. Each of the pharmacokinetic processes—drug absorption, drug distribution, drug metabolism, and drug excretion—is affected to some degree by the aging process. LO 3.2
D RUG A BSORPTION With age there is a decrease in blood flow to the intestinal tract, reduced intestinal absorptive surface area, a decrease in gastric acid secretion, and a decrease in intestinal motility. These changes tend to slow the rate of drug absorption and the onset of drug action. In addition, the peak drug blood level (highest drug concentration attained after administration) may be lower than it would be in a younger adult. While the peak drug level may be lower, the total amount of drug absorbed is usually not significantly affected. Consequently, the main effect of aging is to slow drug absorption and delay the onset of drug action.
Drug Distribution There are significant alterations in body composition that occur with age. The percentage of lean body mass (muscle) and the percentage of total body water decrease. If one thinks of the body as a big beaker filled with 35 liters (l) of fluid and a drug dose dumped into the beaker, there will be a certain concentration of drug per liter. As the percentage of water decreases, the same dose will Chapter 3 • Geriatric Pharmacology
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produce a higher concentration of drug in the beaker. The same thing occurs in the body. As one becomes older, the same dosage of drug given to a younger adult will produce a higher drug concentration in the elderly. The percentage of body fat (adipose tissue) increases with age. This causes lipid-soluble drugs to be more widely distributed to the body organs that have a high fat content, such as adipose tissue and muscle (modest fat content, but large mass), and away from the liver and kidneys. Since the liver and kidneys are responsible for drug metabolism and excretion, any diversion from them will slow elimination of the drug from the body. The drug will then have a longer half-life and duration of action. Water-soluble drugs will have less body fluid in which to dissolve and are less widely distributed out to the organs with high fat content. This produces higher plasma drug levels and greater pharmacological effects when compared to the same dosage of drug administered to a younger adult. The concentration of plasma proteins, mainly albumin, decreases with age. Since most drugs are bound to some extent to plasma proteins and it is only the concentration of “free drug” that produces the pharmacological effect, any decrease in plasma proteins and plasma protein drug binding will increase the amount of free drug (unbound) and, therefore, the intensity of drug effect. In summary, the overall effect of aging on drug distribution is to generally make any adult drug dosage produce greater pharmacological effects in the elderly if the drug is given in the same dosage. Drugs that are affected by the changes in drug distribution with age usually require a reduction in dosage. LO 3.3
D RUG M ETABOLISM AND E XCRETION In general, the rate of drug metabolism decreases with age, although there is much variability. The age-related decreases in liver blood flow and production of some drug microsomal metabolizing enzymes (DMMS) reduce the rate of drug metabolism. The enzymes that are most affected appear to be the enzymes that oxidize drugs, referred to as the mixed-function oxidase system. The pharmacological effects of drugs requiring oxidation, the benzodiazepines (diazepam, Valium) for example, are usually prolonged. In addition, drugs that normally undergo first-pass metabolism are not as extensively metabolized during the first pass through the liver. This allows a greater amount of drug to be absorbed, an example of increased bioavailability. Other factors such as smoking, alcohol consumption, and the administration 38
of certain drugs, all of which may cause microsomal enzyme induction, will increase the rate of drug metabolism. Consequently, it is difficult to accurately predict the effects of aging on specific drug metabolism, but the expected effect is a reduction in the rate of metabolism and an increase in the duration of drug action.
Drug Excretion Drugs are eliminated from the body mainly by renal excretion and gastrointestinal elimination. Some drugs and drug metabolites pass from the liver through the biliary tract and into the intestinal tract for elimination. A few drugs are able to be reabsorbed from the intestinal tract back through the portal system to the liver. This pathway may be repeated and is referred to as enterohepatic recycling. Enterohepatic recycling can increase the drug half-life and the duration of drug action. The reduction of renal blood flow with age has a significant effect on the renal elimination of drugs. Renal excretion is probably the most important pharmacokinetic process that is affected by age. Almost all measures of renal function, such as glomerular filtration rate and creatinine clearance, are significantly reduced with age. The duration of drug action, plasma drug concentration, and pharmacological effects will all be increased for drugs that are eliminated primarily by renal excretion. Drugs that are primarily excreted by the urinary tract usually require dosage reduction. The reduction in dosage is usually based on the urinary excretion of creatinine. Creatinine is a product of muscle metabolism that is excreted by the kidneys in proportion to glomerular filtration rate. The lab test to evaluate the ability of the kidneys to excrete creatinine is known as creatinine clearance. The test involves measuring the concentration of creatinine in the blood and using a mathematical formula to determine the creatinine clearance rate. This value is then compared to the expected normal value found in healthy younger adults. Dosage adjustments can then be calculated based on the level of individual renal function. The plasma concentration of creatinine increases with age and renal disease, and reflects the effects of age and disease to decreased renal function. Table 3:1 summarizes the major effects and consequences of aging on the pharmacokinetic processes. LO 3.4
E FFECTS OF AGE ON D RUG R ESPONSE The effects of age on drug response are difficult to evaluate. Most of the information comes from observations that a specific drug or drug class appears to produce
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Table 3:1
Age-Related Changes in Pharmacokinetic Processes Pharmacokinetic process
Age-related change
Drug absorption
Decreased intestinal blood flow, surface area, and motility delay drug absorption and slow onset of drug action
Drug distribution
Decreased body water, lean body mass, and plasma proteins along with increased fat content increase plasma drug concentrations and pharmacologic effects
Drug metabolism
Decreased liver blood flow, liver organ size, and enzyme concentrations decrease the rate of drug metabolism and increase the duration and intensity of drug action
Drug excretion
Age-related decreases in renal function and blood flow slow the rate of drug excretion and increase the duration and intensity of drug action
either increased or decreased pharmacological effects in geriatric patients when compared to the effects produced in younger adults. Increased pharmacological effects are more common and usually observed as an increase in adverse or toxic effects. The changes in drug sensitivity may be caused by a number of factors: general state of health, nutritional status, presence of chronic disease, and alteration in the pharmacodynamic response to specific drugs.
Nutritional Status Nutrition is extremely important to the state of health. Many of the elderly live alone or in unfamiliar surroundings such as nursing homes. The desire, ability, and affordability to prepare well-balanced meals are often lacking. An adequate diet is important in relation to liver function and the ability to metabolize drugs. Lack of adequate protein intake lowers the concentration of plasma proteins, especially albumin, necessary for plasma protein drug binding. Protein intake is also important for synthesis of drug-metabolizing enzymes. Protein deficiencies may increase the concentrations of “free drug” (unbound) and reduce the rate of drug metabolism, both of which can increase the duration and intensity of drug action. General health and the ability of the body to maintain homeostatic mechanisms such as regulation of body temperature, blood pressure, cardiac output, and many other physiological processes are dependent in part on proper nutrition. Nutritional deficiencies also increase susceptibility to infection, disease, and the adverse effects of drug treatment.
Presence of Disease The major chronic diseases of aging—hypertension, coronary artery disease, diabetes, cancer, and many others—all have effects that reduce vital organ function, especially of the heart, liver, and kidneys. Reduction of organ function decreases the ability of these organs to metabolize and eliminate drugs. Consequently, the actions and adverse effects of most drugs are increased. The consequences of disease on drug action increase as the number of diseases in any one individual increase. Table 3:2 lists the main effect of some of the more common disease-drug interactions.
Alteration of Pharmacodynamic Response It is very difficult to evaluate changes in drug response that are not related to changes in the pharmacokinetic processes. While there may be some decreases in the number of drug receptors or drug receptor sensitivity with age, there are very few examples that have been well documented. One example that is often mentioned is a decrease in sensitivity of the elderly to beta-adrenergic drugs. It appears that actually more of a drug, such as isoproterenol, is required to increase the heart rate of elderly individuals. However, in most cases the elderly are more sensitive to the actions of drugs and experience greater pharmacological effects and higher incidences of adverse effects. The elderly are often more sensitive to drugs that depress the central nervous system. Sedatives, hypnotics, antianxiety agents, antipsychotics, and antidepressant drugs Chapter 3 • Geriatric Pharmacology
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Table 3:2
Common Disease-Drug Interactions in the Elderly Disease
Drugs
Consequence
Congestive heart failure
Cardiac depressants: beta-blockers, some calcium blockers (verapamil, diltiazam)
Excessive cardiac depression, hypotension, cardiac arrest
Diabetes mellitis
Thiazide and loop diuretics, beta-blockers
Alteration of blood glucose
Hypertension
Nonsteroidal antiinflammatory drugs
Interfere with antihypertensive actions of diuretics and *ACE inhibitors
Hypokalemia
Thiazide and loop diuretics, cardiac glycosides (digoxin)
Increase loss of potassium and may cause cardiac arrhythmias
Mental depression
**CNS depressants, propranolol, antihypertensives causing CNS depression (clonidine)
Increase mental depression, precipitate depressive episodes
Prostatic hypertrophy
Anticholinergic drugs
Increase difficulty of urination, urinary retention
Renal disease
Nonsteroidal antiinflammatory drugs, aminoglycosides, amphotericin B
Decrease renal function, may cause renal failure
Respiratory diseases, bronchitis, emphysema
Nonselective beta-blockers
Bronchoconstriction, respiratory distress
Abbreviations: *ACE, angiotensin–converting enzyme; **CNS, central nervous system.
often cause excessive pharmacological and adverse effects in the elderly. This is often in the form of mental confusion, disorientation, and other neurological disturbances. Some of the antipsychotic, antidepressant, and antihistamine drugs possess anticholinergic activity (Chapter 7). Excessive anticholinergic effects frequently cause urinary retention, constipation, and a variety of neurological disturbances. There are many examples of drugs that require special consideration when prescribed for the elderly. Additional geriatric considerations with specific drugs will be presented in the appropriate chapters. LO 3.5
D RUG C OMPLIANCE IN THE E LDERLY Drug compliance is extremely important in the elderly. The elderly are frequently confused by their dosing regimens. They often have difficulty understanding 40
and remembering what the drug is and exactly why it was prescribed. The confusion is increased in those who already have problems with memory, who live alone, and who are not provided with sufficient time for instruction and training on the proper procedures for drug administration. The confusion increases in direct proportion to the number of different drugs and administration devices with which the individual is confronted. The term polypharmacy is used to describe the situation that involves multiple drug prescriptions. Forgetting to take the drug or not remembering whether or not the drug was already taken is the cause of many missed doses. The presence of unpleasant drug side effects also encourages noncompliance. Since physicians are often too busy to take the time to instruct patients, this is one of the important functions of allied health personnel. Time and patience are of extreme importance in these instructions. The attitude and demeanor of the person providing drug prescribing
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instructions are sometimes the key ingredients to successful drug compliance (Figure 3.1). Another important consideration for compliance is the dosage form; for example, liquid, capsule, or tablet. Many elderly patients have difficulty swallowing large capsules. In addition, they often cannot get the lid off the drug container. There are easy-to-open lids for the elderly, available upon request. The elderly often have trouble reading the small print on drug labels or identifying the different drugs. Sometimes describing the different drugs (the small white one, the large green one, etc.) may help them know which drugs to take at the proper times. Organizing a schedule of specific times for drug dosing, such as before a specific meal or just before bedtime, is also important for establishing a routine that is less likely to be forgotten.
Figure 3.1 Home care nurse explaining medication to patient and spouse.
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Chapter Review Understanding Terminology Match the appropriate answer, a or b, with the numbered statement in relationship to drug use in the elderly. (LO 3.1, LO 3.2, LO 3.3, LO 3.4, LO 3.5) a. Increased duration and/or intensity of drug action b. Decreased duration and/or intensity of drug action ___ 1. Cirrhosis of the liver ___ 2. Drug noncompliance ___ 3. An increase in creatinine levels in the blood ___ 4. Drugs that cause microsomal enzyme induction ___ 5. Renal disease ___ 6. Malnutrition ___ 7. Drugs that increase liver blood flow ___ 8. Enterohepatic recycling of drugs ___ 9. Decrease in plasma proteins ___ 10. Lipid-soluble drugs
Acquiring Knowledge Answer the following questions. 11. Describe three changes in body composition that occur with aging. (LO 3.1) 12. What are the major age-related changes that occur in the liver? (LO 3.3) 13. Briefly explain the importance of creatinine in relation to renal function. (LO 3.3) 14. Describe three factors of drug compliance that are relative to geriatric patients. LO 3.5) 15. What are adverse effects of excessive anticholinergic drug action in the elderly? (LO 3.4) 16. Explain how lower concentrations of plasma proteins can increase drug response. (LO 3.2)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. Mr. Green is 75 years old and in the doctor’s office for his first checkup after being prescribed digoxin (Lanoxin) once daily and chlorothiazide (Diuril ) two times a day (BID) for congestive heart failure. He still has some signs of heart failure and has admitted that he sometimes forgets to take his pills. He also has trouble reading the labels and isn’t sure which pill he is supposed to take again at night. Can you give some instructions that might help Mr. Green become more compliant? (LO 3.5) 2. Mrs. Jones is 68 years old and has a history of diabetes and hypertension for which she takes medication. Over the years the diabetes seems to be decreasing her kidney function, and lately her urine samples show the presence of protein. She has recently experienced episodes of dizziness and her blood pressure recording during her checkup today was quite low. Could Mrs. Jones’s blood pressure medication dosage be too high? What might be occurring here that may need some adjustment? (LO 3.4) 3. Mr. Smith has a cancer tumor that has become resistant to chemotherapy. He has experienced dramatic weight loss and his appetite is poor. Medications for his heart condition that were well tolerated in the past have now begun to cause toxicity. List the factors that may be responsible for this recent increase in drug toxicity. (LO 3.3)
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4. Explain how the development of congestive heart failure could lead to a decrease in the rate of drug metabolism and drug excretion. (LO 3.4)
Multiple Choice Use your critical-thinking skills to answer the following questions. 1. The main effect of aging on drug absorption is (LO 3.2) A. increased intestinal surface area B. increased onset of action C. slowing of drug absorption D. increased blood flow to intestines 2. Drug distribution is affected with aging due to (LO 3.2) A. increased lean body mass B. decreased total body water C. decreased percentage of body fat D. increased concentration of plasma proteins 3. The measurement of creatinine can be used to evaluate (LO 3.3) A. liver function B. renal function C. cardiac function D. intestinal function 4. Select the factor that would not cause a decrease in drug metabolism in the elderly. (LO 3.4) A. increased liver blood flow B. decreased drug microsomal enzymes C. reduced liver organ size D. decreased cardiac output 5. Nutritional deficiencies, particularly decreased protein intake, can (LO 3.4) A. increase plasma protein concentration B. decrease concentration of unbound free drug C. decrease drug metabolizing enzymes D. decrease duration and intensity of drug action
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Select the factors of aging that affect the distribution of drugs. (LO 3.2) A. increased renal function B. decreased intestinal blood flow C. increased fat content D. decreased lean body mass 2. Which of the following drugs interact with renal disease to decrease renal function? (LO 3.4) A. aminoglycosides B. nonselective beta-blockers C. cardiac glycosides D. nonsteroidal antiinflammatories
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Chapter Review Continued 3. Age-related physiological changes that occur in humans include (LO 3.1) A. decreased cardiac output B. decrease in organ size C. decreased blood flow to the liver D. fewer cells to carry out organ functions 4. Changes to which pharmacokinetic processes lead to longer duration of action of drugs? (LO 3.3) A. excretion B. distribution C. metabolism D. absorption 5. Factors that affect patient compliance include which of the following? (LO 3.5) A. creatinine clearance B. polypharmacy C. dosage form D. enterohepatic recycling
Sequencing Place the following in order, first to last, of the processes that occur in the body. (LO 3.4)
________________
________________
________________
First
________________ Last
Reduced rate of drug metabolism Increased duration of drug action Inadequate protein intake Decreased plasma protein concentration
Classification Place the following age-related changes under the pharmacokinetic phase they affect. (LO 3.2, LO 3.3) Decreased intestinal motility
Decrease in liver size
Decreased body water
Decreased blood flow to kidneys
Decreased plasma proteins
Decreased enzyme production
Decreased glomerular filtration
Decreased gastric acid secretion
Absorption
Distribution
Metabolism
Excretion
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Chapter 4
M ath R eview and D osage C alculations KEY TERMS decimal: another way to write a fraction when the denominator is 10, 100, 1000, and so on. denominator: bottom number of a fraction; shows the number of parts in a whole. fraction: part of a whole. improper fraction: fraction that has a value equal to or greater than 1. mixed number: number written with both a whole number and a fraction. numerator: top number of a fraction; shows the part. percent: decimal fraction with a denominator of 100. proper fraction: fraction that has a value less than 1. proportion: a mathematical equation that expresses the equality between two ratios. ratio: the relationship of one number to another expressed by whole numbers (1:5) or as a fraction (15 ). solute: substance dissolved in a solvent; usually present in a lesser amount. solution: homogeneous mixture of two or more substances. solvent: liquid portion of a solution that is capable of dissolving another substance.
Learning Outcomes
After studying this chapter, you should be able to
4.4 solve drug problems involving solutions and solid dosage forms.
4.1 solve basic arithmetical problems involving fractions, decimals, and percents.
4.5 solve problems involving pediatric dosing. 4.6 understand the monitoring of IV infusion rates.
4.2 write ratio and proportion equations and solve for the unknown term. 4.3 illustrate conversions from one metric unit of measure to another.
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Introduction
Because the intensity of drug response is directly related to dosage (dose-response relationship), administration of the proper drug dosage is essential to the practice of medicine. Drugs whose names look alike or sound alike (for example, Demerol/dicumarol, Isordil/isuprel) can cause improper drug selection. Mistakes in dosage calculation can cause insufficient drug response or excessive and potentially harmful drug effects. Consequently, it is essential for anyone responsible for administering medication to understand the proper procedures for dosage calculation. This chapter provides a brief review of math and dosage calculations in order to demonstrate the basic principles involved in these calculations. Programs requiring an extensive background in pharmacy and dosage calculations should consult textbooks devoted to this subject.
LO 4.1
F RACTIONS, D ECIMALS, AND P ERCENTS A brief review of fractions, decimals, and percents is presented to refresh the memory for the basic arithmetical procedures used in dosage calculation.
5 51 5 5 11 51 6 6
Fractions When something is divided into equal parts, one of the parts is referred to as a fraction (part of the whole). A fraction is composed of two numbers, a numerator and a denominator. The numerator is the top number of a fraction. It indicates how many parts are being referred to. The denominator is the bottom number of a fraction. It indicates how many parts something has been divided into.
Proper Fractions Fractions whose values are less than 1 (the numerator is smaller than the denominator) are called proper fractions. The following are examples of proper fractions: 1 4
2 3
7 8
9 10
Improper Fractions Fractions whose values are equal to or greater than 1 (the numerator is equal to or greater than the denominator) are called improper fractions. The following fractions are improper: 5 5
7 5
11 6
15 8
An improper fraction can be written as a mixed number, which is a whole number plus the fractional remainder. This is calculated by dividing the denominator of the improper fraction into the numerator and 46
placing any remainder over the original denominator. If there is no remainder, the improper fraction is a whole number: 7 2 51 5 5 24 53 8
The terms of a fraction can be changed without changing its value. Multiplying or dividing the numerator and the denominator of a fraction by the same number does not change the value of the fraction, as shown in the following examples: 242 1 5 442 2
233 6 5 4 3 3 12
Fractions are generally written in their reduced, or lowest, terms. For example: 1 6 reduces to 12 2
Reducing Fractions to Their Lowest Terms Reduce a fraction to its lowest terms by dividing the numerator and denominator by the largest number that will divide into both of them evenly. For example: 15 5 3 4 5 20 5 4
35 7 5 4 5 49 7 7
Multiplying Fractions Multiply fractions by multiplying the numerators together and the denominators together and reducing to lowest terms. For example: 2 3 6 1 3 5 5 3 4 12 2
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If the fractions involve large numbers, reduce the numbers by dividing any numerator and any denominator by the same number. Repeat this cancellation process as often as possible. For example: 1
1
9 27 1 3 5 18 54 4 2
1
1 5 0.005 5 5 1000 200 T thousandths
1 2
Multiplying Decimals
4 2
To multiply a whole number by a fraction, place the whole number over a denominator of 1 and then multiply numerators and denominators. For example: 1 10 1 10 10 3 5 3 5 5 5 2 1 2 2
Dividing Fractions
Multiplying decimals is similar to multiplying whole numbers except for the placement of the decimal point. After multiplying the two decimal numbers, add the total number of decimal places (places to the right of each decimal point) and count off the total number of decimal places in the answer (product). Count from right to left, and put the decimal point in front of the last number you count. For example: 1.25 3 0.25 625 250 0.3125
Dividing one fraction by another is similar to multiplying fractions. However, first you must invert the divisor before multiplying the numerators together and the denominators together. For example:
( 4 decimal places )
0.5 ( 1 decimal place ) 3 0.1 ( 1 decimal place ) 0.05 ( 2 decimal places )
If the divisor is a whole number, place it over 1, invert it, and then multiply as before. For example: 3 3 4 3 1 3 445 4 5 3 5 4 4 1 4 4 16
Decimals Any whole number may be divided into tenths (0.1), hundredths (0.01), thousandths (0.001), and so on. These divisions of a number by orders of 10 (10, 100, 1000 etc.) are known as decimal fractions, or decimals. Decimals are another way of expressing fractions. For example: 1 5 0.01 100
( 2 decimal places ) ( 2 decimal places )
When an answer has fewer numbers than total decimal places, add zeros as placeholders to make up the difference.
2 3 4 3 4 2 4 8 3 5 3 3 9
1 5 0.1 10
25 1 0.25 5 5 100 4 T hundredths
5 1 0.5 5 5 10 2 T tenths
2
4 12 1 3 5 6 16 2 1
corresponds to the last place of the decimal and reduce to lowest terms. For example:
Dividing Decimals When dividing decimals, move the decimal place in the divisor to the far right and then move the decimal place in the number being divided by the same number of places. For example: 500.0 25 4 0.05 5 0.05q25.000 ( 2 places )
0.02 0.010 4 0.5 5 .5q0.010 ( 1 place )
1 5 0.001 1000
To change a fraction to a decimal, simply divide the numerator by the denominator. Note that you may need to add zeros after the decimal point in the dividend. For example: 0.25 1 5 4q1.00 5 0.25 4
To change a decimal to a fraction, place the decimal number over the order of 10 (10, 100, 1000, etc.) that
( 2 places )
( 1 place )
Percents Percent means per hundred. So, percents are decimal fractions with denominators of 100. See the following examples: 10% 5
10 5 0.10 100
25% 5
1 25 5 5 0.25 100 4
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Multiplying Percents Change the percent to a decimal (in hundredths) and multiply. For example: 15 percent of 75
0.2 percent of 50
75 50 3 0.15 (2 decimal 3 0.002 ( 3 decimal places ) 0.100 ( 3 decimal places ) 375 places) 75 11.25 ( 2 decimal places ) LO 4.2
D OSAGE CALCULATIONS Health professionals today are very fortunate because pharmaceutical manufacturers prepare and market most drugs in convenient dosage forms. The metric system has essentially replaced the apothecary system, so mathematical conversions are rarely necessary. Also, the concept of unit dose packaging eliminates much of the time that was previously required for drug calculation and preparation. However, in certain situations, drug calculations are still required. These situations primarily involve the preparation of a drug dosage from a stock solution, vial, scored tablet, or calculation of dosage based on body weight or other body measurement.
Basic Calculations Ratio is the relationship of one number to another expressed by whole numbers (1:5) or as a fraction ( 15 ) . The lowest form of the ratio is determined by dividing the smaller number into the larger number. In this example, the ratio would be 5:1. Proportion is a mathematical equation that expresses the equality between two ratios. EXAMPLE 25:5 = 50:10 The first (25) and last terms (10) are called the extremes. The second (5) and third terms (50) are called the means. The product (multiplication) of the extremes must equal the product of the means. means 25:5 5 50:10 extremes 25 3 10 5 5 3 50 250 5 250
When one of the numbers in the proportion is not known, the proportion equation can be solved for the unknown (referred to as X ). 48
EXAMPLE There are 10 milligrams (mg) of drug per milliliter (ml) of solution. How many milliliters must be administered in order to provide 65 mg of drug? 10 mg:1 ml (what you know) = 65 mg:X ml (what you need to know) 10X 5 65 X 5 6.5 ml
Remember, the smaller known ratio is put to the left of the equal sign and the unknown ratio is put to the right of the equal sign. Solve for X by multiplying the means and the extremes. LO 4.3
S YSTEMS OF M EASUREMENT Metric System The metric system is the preferred system for scientific measurement. The units of measure for the metric system are meter (length), gram (weight), and liter (volume). A convenient feature of the metric system is that measurements are in decimal progression, so that 10 units of one size equal 1 unit of the nexthigher size. The names of the metric system are formed by joining Greek and Latin prefixes with the terms meter, gram, and liter: 1 ( 0.001 ) 1000 1 ( 0.01 ) centi— 100 1 deci — ( 0.1 ) 10
milli—
deka—10 hecto—100 kilo—1000
Apothecary System The apothecary system is an older system of measurement that is being phased out and rarely used today. The basic unit of measurement is the grain (gr). Only a few conversion values are included in this chapter to show the relationship to the metric system.
Household System The household system is a less accurate system of measurement. It is mainly used in the home where dosages can be expressed in terms of common household measurements: teaspoon (tsp), tablespoon (tbsp), and liquid ounces (oz).
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Conversion Tables Weights
EXAMPLE
Convert 750 ml to liters (l). 1000 ml 750 ml 5 1l Xl 1000 X 5 750 750 X5 1000 X 5 0.75 l
1 kilogram (kg) = 1000 grams (g) 1 gram (g) = 1000 milligrams (mg) 1 milligram (mg) = 1000 micrograms (mcg) 1 grain (gr, apothecary system) = 60.0 mg 1 2 grain (gr, apothecary system) = 30.0 mg EXAMPLE
Volumes 1 liter (l) = 1000 milliliters (ml), 1000 cubic centimeters (cc), or approximately 1 quart 500 ml = approximately 1 pint 250 ml = approximately 8 fluid ounces = 1 cup 30.0 ml = approximately 1 fluid ounce 1.0 ml = 1.0 cc (cubic centimeters)
Convert 0.25 g to milligrams (mg). 1g
0.25 5 1000 mg X mg X 5 1000 3 0.25 X 5 250 mg
EXAMPLE
Convert 350 mg to grams (g). 1000 mg
Sometimes it is necessary to convert from one system of measurement to another. EXAMPLE
Convert 500 ml to ounces (oz). 250 ml 500 ml 5 8 oz X oz 250 X 5 500 3 8
Conversions It is frequently necessary to make conversions of solution concentrations from liters (l) to milliliters (ml) and drug weights from grams (g) to milligrams (mg) or micrograms (mcg). Knowledge of metric system equivalents is essential to performing these simple conversions. Conversion problems can be set up as a proportion and solved for X. EXAMPLE
Convert 1.5 liters (l) to ml. 1 l:1000 ml 5 1.5 l:X 1 X 5 1500 ml X 5 1500 ml
Alternate setup of proportion equation as a fraction: EXAMPLE
Convert 1.5 liters to ml. 1l 1.5 l 5 1000 ml X ml X 5 1000 3 1.5 X 5 1500 ml
350 mg
1g Xg 1000 X 5 350 350 X5 1000 X 5 0.35 g
Approximate Household Measures 60 drops (gtt) = 1 teaspoon (tsp) 1 teaspoonful (tsp) = approximately 5.0 ml 1 tablespoonful (tbsp) = approximately 15.0 ml 2 tablespoons (tbsp) = approximately 1 fluid ounce (oz) 1 measuring cup = approximately 8 fluid ounces (oz)
5
250 X 5 4000 X 5 16 oz
PRACTICE PROBLEMS Convert the following: 1. 500 mg = _____ g 2. 0.45 g = _____ mg 3. 0.03 l = _____ ml 4. 4 tbsp = _____ ml 5. 60 ml = _____ oz Solve the following conversions by setting up a proportion equation: 6. 6 teaspoons (tsp) to tablespoons (tbsp) 7. 1.5 pints to ml 8. 5 grains (gr) to mg 9. 500 micrograms (mcg) to mg 10. 2500 grams (g) to kg
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Solutions A solution is a homogeneous mixture of two or more substances. The liquid portion of the solution is known as the solvent and the substance dissolved within the solvent is the solute. Solutions are commonly expressed as percentages (based on 100). There are three types of percentage solutions:
Weight in Weight (W/W) Weight in weight solutions contain a given weight of drug (or other solute) in a definite weight of solvent so that the final solution is 100 parts by weight.
Calculate the number of ml required to administer a dosage of 20 mg of morphine sulfate. 8 mg
20 mg 5 1 ml X ml 8 X 5 20 X 5 2.5 ml
EXAMPLE There is a drug order for 50 mg of secobarbital (elixir). The stock bottle contains 22 mg of secobarbital in 5 ml of solution. How many milliliters should the patient receive? 22 mg
EXAMPLE A 10 percent (W/W) solution of sodium chloride would contain 10 g of sodium chloride in 90 g of water.
Weight in Volume (W/V) Weight in volume solutions contain a given weight of solute (drugs, salts) in enough solvent so that the final solution contains 100 parts by volume. EXAMPLE A 10 percent (W/V) solution of sodium chloride would contain 10 g of sodium chloride in enough water to make 100 ml of final solution.
Volume in Volume (V/V) Volume in volume solutions contain a definite volume of solute added to enough water so that the final solution would be 100 parts by volume. EXAMPLE A 10 percent (V/V) solution of sodium chloride would contain 10 ml of sodium chloride (100 percent solution) in enough water to make 100 ml of final solution.
LO 4.4
CALCULATING DOSAGES The proportion equation is useful for calculating dosages. Whenever three of the terms of a proportion are known, the unknown term can be determined if the equation is properly constructed. EXAMPLE Morphine sulfate injection for intravenous use is available in a concentration of 8 mg/ml of solution.
50
5
50 mg
5 ml X ml 22 X 5 50 3 5 22 X 5 250 X 5 11.3636, or 11.4 ml
EXAMPLE There is a drug order for 75 mg of meperidine (Demerol) to be administered intramuscularly (IM). Demerol is supplied in a 5 percent solution (W/V). A 5 percent solution (W/V) would be 5 g of Demerol in 100 cc or 50 mg/1 ml as it is written on the vial label. How many ml of Demerol should be administered to the patient? 50 mg
5
75 mg
1 ml X ml 50 X 5 75 75 X5 50 X 5 1.5 ml
EXAMPLE Insulin is usually administered in a syringe (U-50 or U-100) that corresponds to the concentration of the insulin stock solution of 100 units per ml (U-100). If an insulin syringe is not available, a tuberculin syringe may be used (Figure 4.1). However, the unit dosage must be converted to ml using the proportion method. What would be the dose in milliliters for an order of 20 units of insulin U-100? 100 units 20 units 5 1 ml X ml 100 X 5 20 20 X5 100 X 5 0.2 ml
EXAMPLE There is a drug order for 60 mg of drug. The drug is available in 20-mg tablets. How many tablets
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Figure 4.1
Standard Insulin (U-100, U-50) and Tuberculin Syringes Used for Subcutaneous Injection of Insulin 1 cc or ml 100 units
0.5 cc or ml 50 units
(a) Insulin
1 cc or ml
(b) Insulin (c) Tuberculin
LO 4.5
are required? The problem requires setting up a fraction based on the formula: 3
desired dosage available dosage
5
60 mg 20 mg ( 1 tablet )
5 3 tablets
1
A variation on this problem could be that 10 mg of a drug are desired: 1
desired dosage available dosage
5
10 mg 20 mg ( 1 tablet )
1 5 tablet 2
2
(tablet must be scored for breakage)
PEDIATRIC DOSAGE CALCULATIONS Dosage calculations in pediatrics are based on age, body surface area (BSA), and body weight. BSA and body weight are the methods most frequently used to calculate pediatric dosages. Following are the formulas used for these calculations. Clark’s rule: weight of child 150 lb
Fried’s rule: age in months 150
EXAMPLE An injection of 1000 units of tetanus antitoxin is ordered. The tetanus antitoxin is available in an ampule labeled 1500 units/ml. How many milliliters should be injected? desired dosage available dosage
3 adult dose 5 child’s dose
3
average 5 child’s dose adult dose
Body surface area (BSA) rule: body surface area of child ( square meters ) 1.7
3 adult dose 5 child’s dose
2
5
1000 units 1500 units ( per milliliter ) 3
0.66 ml 2 5 ml 5 3q2.00 3
EXAMPLE Katie has just turned 3 years old and weighs 30 pounds. Her mother wants to know how much cough syrup to give Katie. The directions have worn off the bottle and she can only make out the dosage for
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adults—2 teaspoons every 4 hours. How much should Katie receive? 30 Clark’s rule: 150 3 10 ml 5 Katie’s dose 1 5 3 10 ml 5 2 ml 36 Fried’s rule: 150 3 10 ml 5 Katie’s dose 0.24 3 10 ml 5 2.4 ml
Dosage Calculations Based on Body Weight Drug dosages are sometimes administered on a body weight basis, for example, in mg/kg. This may require conversion of pounds to kilograms (1 kg = 2.2 lbs). The dose/kg is then multiplied by the number of kilograms. EXAMPLE There is a drug order for the antibiotic amikacin 7.5mg/kg administered intravenously (IV) for a patient weighing 110 pounds. Amikacin is available as 100 mg per 2-ml vial. How many milligrams of drug are required and in what volume? Step 1: Convert pounds to kilograms. 110 lbs divided by 2.2 lb/kg 5 50 kg
Step 2: Determine how many mg of drug are required. 7.5 mg/kg 3 50 kg 5 375 mg
Step 3: Determine how many ml of stock solution contains 375 mg, using the proportion equation method. 100 mg:2 ml 5 375 mg:X ml 100 X 5 ( 375 ) ( 2 ) or 750 X 5 750/100 5 7.5 ml of vial solution ( 3 34 vials )
EXAMPLE If the patient in the previous problem was an infant weighing 20 lbs with a body surface area of 0.44 square meter, what would be the dose according to the BSA rule? BSA rule: BSA of child (square meters)/1.7 × adult dose 0.44 1.7
100 mg 2 ml
5
100 mg 2 ml ,
calculate volume
97 mg X ml
100 X 5 ( 2 ) ( 97 ) or 194 X 5 1.94 ml of vial solution
52
132 lbs divided by 2.2 lb/kg 5 60 kg
Step 2: Determine how many micrograms are required. 60 kg 3 10 mcg/kg 5 600 mcg or 0.6 mg
Step 3: Determine how many capsules are required. 0.2 mg:capsule 5 0.6 mg:X 0.2 X 5 0.6 X 5 3 capsules of 200 mcg
LO 4.6
M ONITORING IV I NFUSION R ATES Hospitalized patients often receive drug administration by slow IV infusion. Drugs are added to various sterile IV solutions such as sodium chloride injection, United States Pharmacopeia (USP), or dextrose (5%) injection, USP. Drug concentrations and solutions are prepared by the hospital pharmacy. The IV drug infusion solutions must be prepared under aseptic conditions, the drugs and solutions mixed must be chemically compatible, and often the infusion solution must be adjusted to a specific pH value. Preparation of these solutions should always follow established hospital procedures and be reviewed by a pharmacist. After establishment of an open IV line, the drug solution is administered according to a specific infusion rate, in drops per minute (Figure 4.2). Usually there are 12–15 drops/ml of solution, but this number can vary with the viscosity of different solutions. Since allied health personnel are sometimes called upon to monitor IV infusion rates, the following example is presented to illustrate the principles involved. Formula for adjusting IV infusion rate: ml of IV solution 3 number of drops/ml
3 375 mg
5 0.258 3 375 5 96.75 mg or 97 mg
Since vials contain
EXAMPLE A loading dose of digoxin capsules (Lanoxicaps), 10 mcg/kg, has been ordered for a patient weighing 132 pounds. Lanoxicaps are available as 100- and 200-mcg capsules. How many capsules should be administered? Step 1: Convert pounds to kilograms.
hours of administration 3 60 minutes
5 drops per minute
EXAMPLE An IV infusion of furosemide (Lasix) 2 mg/ min for 4 hours was ordered for a patient with severe edema. The hospital pharmacy prepared the infusion solution by adding 480 mg (2 mg/min × 60 × 4) in 500 ml
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Figure 4.2 Adjusting the Drip Rate for Intravenous infusion
of sodium chloride injection, USP. How many drops per minute should be administered? 500 ml 3 15 drops/ml 4 hours 3 60 minutes
5
7500 5 31.25 drops/min 240
Regulate the IV flow by counting the drops (to nearest whole number) for 15 seconds and multiplying by 4 (for 1 min). Adjust the IV tube clamp until the correct rate is attained.
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Chapter Review Understanding Terminology Match the term in the left column with the appropriate set of examples to the right. Use each set of examples only once. (LO 4.1) a.
8 13 3 , , 16 27 4
b.
15 4 39 , , 12 3 18
___ 1.
Mixed numbers
___ 2.
Decimals
___ 3.
Proper fractions
___ 4.
Denominator
___ 5.
Fractions
___ 6.
Numerator
1 4 17 c. 1 , 15 , 5 2 5 18
___ 7.
Improper fractions
d. 1.5, 0.75, 12.3333
e. the 3 in
3 4
f. the 4 in
3 4
g.
1 7 5 , , 2 10 12
Answer the following question. 8. Define solution, solute, and solvent. (LO 4.4)
Acquiring Knowledge Answer the following questions and solve the following problems. (LO 4.2, LO 4.3, LO 4.4) 1. Convert 0.125 g to milligrams. 2. Convert 1200 ml to liters. 3. Two teaspoons of cough syrup equal how many milliliters? 4. One-quarter grain equals how many milligrams? 5. Four fluid ounces equal how many milliliters? 6. There is a drug order for 2.5 mg of glipizide (Glucotrol). Scored tablets are available in 5- and 10-mg strengths. Calculate the dosage. Why is the drug being given? (Refer to the PDR ®.) 7. After several days, the dosage of glipizide for the patient in Problem 6 has been increased to 7.5 mg. Calculate the dosage. 8. There is an order for 75 mg of Demerol Hydrochloride syrup (USP). The syrup contains 50 mg of Demerol Hydrochloride per 5 ml. Calculate the dosage. What is the generic name of this drug? (Refer to the PDR®.) 9. Several hours later, the patient in Problem 8 complained of severe pain. The order was changed to 100 mg administered by intramuscular (IM) injection. Demerol Hydrochloride is supplied as a solution in vials labeled 50 mg/ml. Calculate the parenteral dosage. 10. A drug vial for parenteral injection is labeled “1 ml contains 50 mg.” Calculate the amount required to administer a 30-mg dose.
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Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. Assume that you’re spending your summer as an intern in a university hospital pharmacy. One of your duties is to prepare desired dosages from available dosages to arrive at the correct weight or number of units of drug for each order the pharmacist fills. Show the calculations for the correct amount of drug for each of the following orders that were filled on your first day of work. (LO 4.3, LO 4.4) a. The first order called for 90 mg of drug. The drug is available in 30-mg tablets. How many tablets are required? b. The second order called for 2000 units of tetanus antitoxin. The tetanus antitoxin is available in an ampule of 1500 units/ml. How many milliliters should be injected? c. The third order called for 70 mg of secobarbital. The stock bottle contains 22 mg of secobarbital in 5 ml of solution. How many milliliters should the patient receive? 2. Bert just finished his training as a pharmacist assistant and started working in a nursing home dispensary last week. One of his job duties is to calculate the number of milliliters of drug-for-drug orders given in milligrams. Show how you would deal with the following patient orders if you had Bert’s job. (LO 4.3, LO 4.4) a. There’s a drug order for 100 mg of Demerol to be administered IM. The label on the stock bottle of Demerol says it’s in a 5 percent solution, or 50 mg per ml. b. There’s an order for a diabetic patient of 30 units of insulin. The stock bottle is labeled U-100, or 100 units per ml. 3. There is a drug order for diazepam (Valium), 0.5 mg/kg, administered orally. The patient weighs 110 pounds. Valium is available in 2-, 5-, and 10-mg tablets. How many milligrams and what combination of tablets will you administer? (LO 4.3, LO 4.4) 4. Ampicillin (Omnipen) oral suspension is available as 125 mg/5 ml. There is a drug order for 500 mg four times a day (QID). How many milliliters will you administer with each dose? How often will you administer the dose? (LO 4.3, LO 4.4) 5. The usual oral dose of ampicillin is 500 mg. How much should a 15-month-old baby receive according to Fried’s rule? How much should a 50-pound child receive according to Clark’s rule? (LO 4.5) 6. There is an order for 1000 ml of normal saline (0.9%) to be administered by IV infusion in 8 hours. The IV tubing delivers 15 drops per ml. How many drops should be administered per minute? (LO 4.6)
Multiple Choice Questions Use your critical-thinking skills to answer the following questions. 1. The correct conversion from metric system to household system is (LO 4.3) A. 5 ml equals 1 tablespoon B. 15 ml equals 1 teaspoon C. 30 ml equals 1 fluid ounce D. 500 ml equals 1 measuring cup 2. Twenty percent (20%) of 90 equals (LO 4.1) A. 12 B. 15 C. 18 D. 21 3. Drug X is to be administered intravenously at a dosage of 20 mg/kg. A patient weighing 60 kg should receive (LO 4.1, LO 4.2) A. 60 mg B. 120 mg C. 600 mg D. 1200 mg Chapter 4 • Chapter Review
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Chapter Review Continued 4. There is a drug order for 75 mg of drug. The drug is available in 30-mg scored tablets. How many tablets should be administered? (LO 4.2) A. 2 C. 3 B. 2½ D. 3½ 5. An analgesic is ordered for intramuscular injection. If the concentration of analgesic available is 8 mg/ml, how many ml should be administered for a dosage of 20 mg? (LO 4.4) A. 2.0 C. 3.0 B. 2.5 D. 3.5
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Select all terms that define a denominator. (LO 4.1) A. part of a whole B. shows the part C. parts in a whole D. decimal fraction 2. Which of the following is the proper way to write the improper fraction 14/4? (LO 4.1) A. 14/4 B. 12⁄4 C. 2½ D. 31⁄4 3. The correct way to divide one-half by five would be which of the following? (LO 4.1) A. multiply ½ by 1⁄5 B. divide ½ by 5 C. divide 1 by 2⁄5 D. divide 1 by 10 4. Select the following terms that are equal. (LO 4.2) A. 25000 mcg B. 25 kg C. 0.025 g D. 0.0025 mg 5. Select the information needed to use Fried’s rule. (LO 4.5) A. height of child B. body surface area C. weight of child D. age in months
Sequencing Organize the following from largest to smallest. (LO 4.3) _______________ Largest
_______________
_______________
_______________ Smallest
milliliter kiloliter deciliter hectoliter
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Classification Place the following examples under the equal term. (LO 4.1) 0.5 2
/3
15
/20
21/ 5
66
0.75
12
/99
/24
½
¾
1½
0.66
2.2
11
6
1.5
/5 One-half
/4
One and one-half
Three-quarters
Two-thirds
Two and one-fifth
Document Exercise Using the prescription below, answer the following questions. (LO 4.3)
Raven Clinic Practice RX 1000 Hospital Avenue Anytown, USA 12345 360-555-1000 NAME:
Jane Doe
DATE:
ADDRESS: RX
Amoxicillin
Sig:
200mg twice daily for 10 days
Dr. Max Sanders
M.D.
Substitution Permitted DEA #:
M.D. Dispense as written REFILL:
NR
1
2
3
4
Stock on hand available: Amoxicillin 250 mg/5 ml in 150-ml and 75-ml bottles a. Calculate the amount needed for one dose. b. What would the total daily dose be? c. Calculate the total needed for the full prescription order. d. Which size of bottle would be most appropriate to dispense and why?
For interactive animations, videos, and assessment visit: www.mcgrawhillconnect.com Chapter 4 • Chapter Review
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2 PART
P harmacology of the P eripheral N ervous S ystem CHAPTER 5 Introduction to the Autonomic Nervous System 60
CHAPTER 6 Drugs Affecting the Sympathetic Nervous System 72
CHAPTER 7 Drugs Affecting the Parasympathetic Nervous System 91
CHAPTER 8 Drugs Affecting the Autonomic Ganglia 107
CHAPTER 9 Skeletal Muscle Relaxants
115
CHAPTER 10 Local Anesthetics 131
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Chapter 5
Introduction to the Autonomic N ervous S ystem KEY TERMS acetylcholine (ACH): neurotransmitter of parasympathetic (cholinergic) nerves; stimulates the cholinergic receptor. adrenergic receptor: receptor located on internal organs that responds to norepinephrine and epinephrine. afferent nerve: transmits sensory information from peripheral organs to the brain and spinal cord (central nervous system). autonomic nervous system (ANS): system of nerves that innervate smooth and cardiac muscle (involuntary) of the internal organs and glands. cholinergic (muscarinic) receptor: receptor located on internal organs and glands that responds to acetylcholine. efferent nerve: carries the appropriate motor response from the brain and spinal cord to the peripheral organs. epinephrine (EPI): hormone from adrenal medulla that stimulates adrenergic receptors, especially during stress. fight or flight reaction: response of the body to intense stress; caused by activation of the sympathetic division of the ANS. homeostasis: normal state of balance among the body’s internal organs. neurotransmitter: substance that stimulates internal organs to produce characteristic changes associated with sympathetic and parasympathetic divisions. norepinephrine (NE): neurotransmitter of sympathetic (adrenergic) nerves that stimulates the adrenergic receptors. parasympathetic: refers to nerves of the ANS that originate in the brain and sacral portion of the spinal cord; they are active when the body is at rest or trying to restore body energy and function. sympathetic: refers to nerves of the ANS that originate from the thoracolumbar portion of the spinal cord; they are active when the body is under stress or when it is exerting energy.
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Learning Outcomes
After studying this chapter, you should be able to
5.4 list the main organ effects caused by parasympathetic stimulation.
5.1 describe the two divisions of the ANS and the main functions of each division.
5.5 describe the different autonomic receptors that are stimulated by acetylcholine, norepinephrine, and epinephrine.
5.2 explain how sympathetic and parasympathetic nerves interact with each other to regulate organ function (maintain homeostasis). 5.3 describe the fight or flight reaction and explain how sympathetic activation affects the activities of the different organs.
Introduction
The primary function of the central nervous system is to control and coordinate the activity of all the systems in the body. The overall activity of the nervous system at any moment depends on neural communication (via nerve impulses) among many areas of the body. The autonomic nervous system is a subdivision of the central nervous system that regulates the activities of the internal organs and glands. The internal organs and glands are under involuntary or unconscious control. Before discussing the pharmacology of the autonomic nervous system, it is helpful to briefly review the general organization of the nervous system and the major anatomic and physiologic features of the autonomic nervous system.
LO 5.1
N ERVOUS S YSTEM O RGANIZATION The nervous system is an elaborate system that functions at both conscious (under control of the will, or voluntary) and unconscious (not under control of the will, or involuntary) levels.
Central Nervous System (CNS) The central nervous system (CNS) consists of the brain and spinal cord. The CNS receives and interprets sensory information (via peripheral afferent nerves) and then initiates appropriate motor responses (via peripheral efferent nerves). The structural and functional features of the brain and spinal cord are presented in Chapter 11.
Peripheral Nervous System (PNS) The peripheral nervous system is composed of 12 pairs of cranial nerves and 31 pairs of spinal nerves. It
is separated into two divisions—the somatic and the visceral—based on the type of muscle to which these nerves travel (innervate).
Somatic Division The somatic nerves are the branches of the cranial and spinal motor nerves that innervate skeletal muscle (voluntary). These nerves are under conscious, or voluntary, control of the cerebral cortex.
Visceral Division (Autonomic Nervous System) The visceral nerves are the branches of the cranial and spinal motor nerves that innervate cardiac and smooth muscle (involuntary) of the internal organs and glands. The visceral nerves, which are not under conscious control, are regulated by the hypothalamus and the medulla oblongata. The visceral nerves are commonly referred to as the autonomic nervous system (ANS). Chapter 5 • Introduction to the Autonomic Nervous System
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LO 5.2
OVERVIEW OF THE ANS It is important to emphasize that understanding the physiology and pharmacology of the ANS can be challenging to beginning students. However, understanding the ANS is essential to understanding the actions of many drugs. The ANS is composed of the nerves that innervate (or travel to) smooth and cardiac muscle. These two types of involuntary muscle are found in the walls of the internal organs and glands and possess a special property, autorhythmicity, which allows them to initiate their own contractions. This process can be demonstrated by removing the heart or a piece of intestine from a frog, placing the organ in oxygenated Ringer’s solution, and observing the contractions that occur without any stimulation. If the internal organs can initiate their own contractions, why is the autonomic nervous system needed? The answer is the key to the purpose of the ANS: the ANS functions to regulate the rate at which these organs work, either increasing or decreasing their activity. In this way, homeostasis, the normal balance among the body’s internal organs, can be maintained. Whether the activity of the organ increases or decreases depends upon body activity. But the question arises, “How can an autonomic nerve going to any visceral organ both increase and decrease the activity of the organ?” The answer is that it cannot. There are two divisions of the autonomic nervous system, the parasympathetic and sympathetic. Generally, each visceral organ receives a nerve from each division. One division usually increases the activity of a particular organ while the other decreases the activity. This is referred to as dual autonomic innervation. LO 5.3
PARASYMPATHETIC AND S YMPATHETIC D IVISIONS The ANS is composed of the parasympathetic and sympathetic divisions. The nerves of the parasympathetic division (also known as the craniosacral division) originate from the brain (cranial nerves 3, 7, 9, and 10) and spinal cord (sacral nerves S2 to S4). The cranial nerves supply the internal organs and glands of the head, thoracic cavity, and upper portion of the abdominal cavity. The sacral nerves supply the lower portion of the abdominal cavity and the pelvic cavity. The origin and distribution of parasympathetic nerves are shown in Figure 5.1. The nerves of the sympathetic division 62
(known as the thoracolumbar division) originate from the thoracic and lumbar spinal nerves (T1 to L3). The thoracic nerves supply the internal organs and glands of the head, thoracic cavity, and upper abdominal cavity. The lumbar nerves supply the lower portion of the abdominal cavity and the pelvic cavity. The origin and distribution of sympathetic nerves are shown in Figure 5.2. As a result, most of the major body organs and glands receive a nerve from each division. There are exceptions; for example, most blood vessels do not receive parasympathetic innervation. In this situation, blood pressure is controlled by either increasing sympathetic activity to cause vasoconstriction or decreasing sympathetic activity to cause vasodilation ( Figure 5.3). However, the general plan is that one division is responsible for increasing the activity of a particular organ, while the other division decreases the activity of that organ. Unfortunately, one division does not always increase activity and the other division always decrease activity in each of the organs. How is the effect of each division predicted? The answer is that sympathetic stimulation produces changes in the body that are similar to changes observed during frightening or emergency situations. These changes are collectively referred to as fight or flight reaction. During the fight or flight reaction, the adrenal medulla releases epinephrine (also known as adrenaline) and some norepinephrine into the blood. These neurotransmitters then act as hormones and travel to all sympathetic receptor sites producing intense sympathetic stimulation. During the fight or flight reaction, the sympathetic division increases the activity of certain organs to allow a greater expenditure of energy for both physical and mental exertion. For example, sympathetic stimulation increases heart rate and the force of myocardial contraction; also bronchodilation allows for more air exchange in the lungs. At the same time, there is a decrease in the activity of the organs whose functions are not required for the fight or flight reaction. For example, activity of the gastrointestinal and urinary tracts is inhibited. The parasympathetic division is more active during periods of rest and restoration of body energy stores. The parasympathetic nerves increase body functions such as digestion and elimination of waste products (urination, defecation). Normally, we do not experience situations in which we need the fight or flight reaction to enable us to fight or run. However, the daily stresses, anxieties, and illnesses we do experience are sufficient to activate the sympathetic system to produce changes that are similar
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Figure 5.1
Schematic of the Parasympathetic Nervous System Showing the Origin and Distribution of Parasympathetic Nerves Preganglionic neurons
Pterygopalatine ganglion
Postganglionic neurons
Ciliary ganglion
Oculomotor n. (CN III) Facial n. (CN VII)
Lacrimal gland Eye
Submandibular ganglion Submandibular salivary gland
Otic ganglion
Parotid salivary gland
Glossopharyngeal n. (CN IX)
Vagus n. (CN X) Heart
Cardiac plexus
Regions of spinal cord Cervical
Pulmonary plexus Esophageal plexus
Lung
Thoracic Lumbar Sacral
Celiac ganglion
Stomach Liver and gallbladder
Abdominal aortic plexus
Spleen Pancreas
Pelvic splanchnic nerves
Kidney and ureter Transverse colon
Inferior hypogastric plexus
Descending colon Small intestine Rectum
Pelvic nerves
Penis
Ovary Uterus
Bladder Scrotum
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Figure 5.2
Schematic of the Sympathetic Nervous System Showing the Origin and Distribution of Sympathetic Nerves
Eye
Pons Salivary glands
Preganglionic neurons Postganglionic neurons Heart
Cardiac and pulmonary plexuses
Regions of spinal cord Cervical Thoracic Lumbar Sacral
Lung
Celiac ganglion
Liver and gallbladder Stomach
Superior mesenteric ganglion
Spleen Pancreas Postganglionic fibers to skin, blood vessels, adipose tissue
Inferior mesenteric ganglion
Small intestine
Large intestine
Rectum
Sympathetic chain ganglia
Adrenal medulla Kidney
Ovary
Penis Uterus
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Scrotum Bladder
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to the fight or flight reaction. When the Figure 5.3 Vasoconstriction and Vasodilation sympathetic division is stimulated, all sympathetic nerves are activated at the same time. Therefore, the whole body is stimulated. With the parasympathetic division, only selected nerves can be Artery stimulated, and the stimulation can be confined to a particular body system, for example, contraction of the urinary 1 bladder during urination. The overall Sympathetic effects of sympathetic and parasympa1 Strong nerve fiber sympathetic thetic stimulation are summarized in tone Table 5:1. 2 Usually in a beginning discussion 2 Smooth muscle of the ANS, only the peripheral motor contraction 3 Vasomotor (efferent) nerves are discussed. Periph3 Vasoconstriction tone eral autonomic nerves are the branches of the cranial and spinal nerves that travel to the cardiac muscle and smooth (a) Vasoconstriction muscle of the internal organs. A typical peripheral nerve is composed of many neurons traveling together to the same destination. In an autonomic nerve, two groups of neurons are linked together 1 by synapses as the nerve travels from the spinal cord to the internal organ. In the peripheral nervous system, a col1 Weaker sympathetic lection of synapses is referred to as a tone 2 ganglion. In the ANS, neurons that emerge 2 Smooth muscle from the spinal cord form the preganrelaxation 3 glionic nerve fiber. Neurons that travel 3 Vasodilation from the ganglion to the internal organ form the postganglionic nerve fiber. The autonomic ganglion is the collection of (b) Vasodilation synapses between the preganglionic and postganglionic nerve fibers, as illustrated in Figure 5.4. (a) Vasoconstriction in response to a high rate of sympathetic nerve The main pharmacological differ- f iring. Vasoconstriction increases blood pressure but reduces blood flow. ence between the sympathetic nerves (b) Vasodilation in response to a low rate of sympathetic nerve firing. decreases blood pressure but increases blood flow. Black and the parasympathetic nerves is the Vasodilation lines across each nerve fiber represent the firing frequency of action neurotransmitter released from the potentials. postganglionic nerve ending of each division. The neurotransmitters bind to and stimulate ganglia is also ACH, but at the postganglionic nerve endvarious autonomic receptor sites (discussed below) that ings, it is norepinephrine (NE). Nerves that release are located on the cell membranes of the internal organs acetylcholine are referred to as cholinergic, while nerves and glands. This produces the characteristic effects that that release norepinephrine are referred to as adrenare associated with each division of the ANS ( Table 5:1). ergic. The cardiac and smooth muscle membrane sites In the parasympathetic nervous system, the neuwhere these neurotransmitters act are known as the rotransmitter released at the ganglia and the postgancholinergic (also known as muscarinic) receptors glionic nerve endings is acetylcholine (ACH). In (ACH) and the adrenergic receptors (NE) as shown sympathetic nerves, the neurotransmitter released at the in Figure 5.5. Chapter 5 • Introduction to the Autonomic Nervous System
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LO 5.4
Table 5:1
Effects of Sympathetic and Parasympathetic Stimulation Organ
Sympathetic effect
Parasympathetic effect
Adrenal medulla
Release of epinephrine
—
Arteries
Vasoconstriction (exceptions are the coronary arteries and arteries to skeletal muscle, which are dilated)
Most arteries are not supplied by parasympathetic nerves
Heart
Increases heart rate and AV conduction
Decreases heart rate and AV conduction
Increases contractility
Slight decrease in contractility
Intestines, GI motility, and secretions
Decreased
Increased
Postganglionic neurotransmitter
Norepinephrine released
Acetylcholine released
Pupil of the eye
Dilation (mydriasis)
Constriction (miosis)
Respiratory passages, lower
Bronchodilation
Bronchoconstriction
Urinary bladder
Relaxation
Contraction
Urinary sphincter
Contraction
Relaxation
Figure 5.4
Diagrammatic Representation of an Autonomic Preganglionic Nerve Fiber
Autonomic efferent innervation ACH
ACH or NE
Preganglionic fiber
Postganglionic fiber
Visceral effectors (cardiac muscle, smooth muscle, glands)
Autonomic ganglion The nerve fiber (emerging from the spinal cord) synapses at an autonomic ganglion with a postganglionic nerve fiber that terminates on an internal organ (heart). In the parasympathetic division, the postganglionic nerve fiber is cholinergic and releases ACH. In the sympathetic division, the postganglionic nerve fiber is adrenergic and releases NE. The neurotransmitter released from preganglionic nerve fibers at the autonomic ganglion of both divisions is ACH.
In summary, the effects of parasympathetic stimulation are produced by the release of acetylcholine, which binds to the cholinergic receptors. The effects of sympathetic stimulation are produced by the release 66
of norepinephrine from adrenergic nerve endings and also by epinephrine (EPI) released from the adrenal medulla. Both norepinephrine and epinephrine bind to and stimulate adrenergic receptors.
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term cholinergic receptor was introduced to refer to the receptor binding of ACH. The older terms, muscarinic and nicotinic, are still used because they (a) Parasympathetic fiber differentiate the different cholinergic sites. MusNicotinic (Nn) carinic receptors are located on the cell memreceptor branes of the visceral organs and glands and are ACH stimulated by ACH released from parasympathetic postganglionic nerve endings. The resultTarget cell ing effects depend on the individual organ; some organ actions are increased (GI tract), while othACH ers are decreased (heart). There are two types Preganglionic Postganglionic Muscarinic of nicotinic receptors: nicotinic-nerve (Nn) and neuron neuron receptor nicotinic-muscle (Nm). Nn receptors are located at both the parasympathetic and sympathetic gan(b) Sympathetic adrenergic fiber glia and are stimulated by ACH released from preganglionic nerve endings to conduct impulses Nicotinic (Nn) receptor across the autonomic ganglia to the postganglionic ACH fibers of both autonomic divisions. Nm receptors are located on cell membranes of skeletal muscle Target and are stimulated by ACH from somatic nerve cell endings to contract skeletal muscle. These Nm receptors are somatic, not autonomic, and will be Preganglionic NE neuron discussed separately in Chapter 9 with the skeletal Postganglionic Adrenergic receptor muscle relaxant drugs. neuron In the sympathetic division, the postganglionic neurons release NE, which stimulates the (a) Parasympathetic pre- and postganglionic neurons releasing adrenergic receptors. The adrenergic receptors ACH on both the ganglionic nicotinic (Nn) and muscarinic (cholinergic) receptors. (b) Sympathetic pre- and postganglionic are divided into alpha and beta receptors. There neurons releasing ACH at the ganglionic nicotinic (Nn) receptor are several subtypes of each. The most important and NE at the adrenergic receptor. with regard to drug actions are the alpha-1, beta-1, and beta-2 receptors. Individual organs usually possess one type of receptor, but there are a few exceptions. The definition or action of alpha-1 recepLO 5.5 tor stimulation is the contraction of smooth muscle; CHOLINERGIC AND for example, vasoconstriction of blood vessels. Beta-1 ADRENERGIC RECEPTORS receptors are located mainly on the heart and mediate The most confusing aspect of autonomic pharmacolcardiac stimulation, an increase in heart rate and force ogy is gaining an understanding of the different cholinof contraction. Beta-2 receptors are located on smooth ergic and adrenergic receptors. What follows is a brief muscle and produce relaxation of smooth muscle; for description and overview of these receptors that will be example, relaxation of respiratory smooth muscle further discussed in the following chapters. (bronchodilation). In the parasympathetic division there are two main There are specific drugs that can selectively bind types of cholinergic receptors: muscarinic and nicotinic. to and stimulate or block the individual cholinergic and These names originate from early pharmacologic studadrenergic receptors. For example, there are alpha-1 agoies with substances (drugs) obtained from mushrooms nist and alpha-1 antagonist drugs, and a variety of beta-1 (muscarine) and tobacco (nicotine). This terminology and beta-2 agonist and antagonist drugs. The effects was established before the discovery of ACH. Muscaproduced by the agonist drugs are opposite to those of rine and nicotine were found to stimulate the activity of the antagonist drugs. Depending on the clinical situadifferent parasympathetic receptors. Following the distion being treated, it is possible to selectively increase or covery of ACH, it was determined that ACH stimulated decrease the function of a particular organ or system. The both the muscarinic and nicotinic receptors and was the following chapters will discuss the individual drug classes neurotransmitter of the parasympathetic division. The and major pharmacologic features. Figure 5.5
Diagrammatic Representation of Parasympathetic and Sympathetic Fibers
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Chapter Review Understanding Terminology Answer the following questions. ___ 1.
What is the difference between an afferent nerve and an efferent nerve? (LO 5.1)
___ 2.
Differentiate between adrenergic receptors and cholinergic receptors. (LO 5.4)
___ 3.
What is the meaning of homeostasis? (LO 5.2)
___ 4.
What terminology is applied to nerves that release acetylcholine? (LO 5.4)
___ 5.
What terminology is applied to nerves that release norepinephrine? (LO 5.4)
Acquiring Knowledge Answer the following questions. 1. What are the two main divisions of the autonomic nervous system? (LO 5.3) 2. What is the main function of each division? (LO 5.3) 3. From what areas of the CNS does each division originate? (LO 5.3) 4. What is the significance of “dual autonomic innervation” to most internal organs? (LO 5.2) 5. What property of smooth and cardiac muscle allows them to initiate their own contractions? (LO 5.2) 6. Describe what is meant by the fight or flight reaction. What conditions activate this reaction? (LO 5.3, 5.4) 7. During what body activities is the parasympathetic division active? (LO 5.3) 8. Think of an emergency situation requiring immediate and intense physical exertion. List as many body organs as you can and predict the desired level of activity (increased or decreased). Which neurotransmitter would produce this effect? Do your predictions correctly correspond to the fight or flight reaction? (LO 5.3, 5.4)
Applying Knowledge on the Job Use your critical thinking skills to answer the following questions. 1. Use the PDR ® product category index to look up drugs that mimic (parasympathomimetics) and drugs that inhibit (parasympatholytics) cholinergic activity. List one or two drugs from each category, the main drug effect, and clinical indications. Do your findings correspond to the expected effects of cholinergic stimulation and inhibition? (LO 5.3, 5.4, 5.5) 2. Use the PDR ® product category index to find drugs that mimic (sympathomimetics) and drugs that inhibit (sympatholytics) adrenergic activity. List one or two drugs, the main drug effect, and clinical indications. Do your findings correspond to the expected effects of adrenergic stimulation and inhibition? (LO 5.3, 5.4, 5.5)
Multiple Choice Questions Use your critical-thinking skills to answer the following questions. 1. Select the nerve–function combination that is correctly matched. (LO 5.1) A. afferent nerve—conducts nerve impulses to peripheral organs B. efferent nerve—conducts sensory nerve impulses C. autonomic nerve—conducts nerve impulses to visceral organs D. adrenergic nerve—conducts nerve impulses to skeletal muscle
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2. Sympathetic activation produces all of the following effects except (LO 5.3) A. relaxation of urinary bladder B. increased heart rate C. pupillary dilation D. bronchoconstriction 3. The sympathetic postganglionic nerve ending releases (LO 5.4) A. epinephrine B. norepinephrine C. acetylcholine D. dopamine 4. The neurotransmitter released at both sympathetic and parasympathetic ganglia is (LO 5.4) A. acetylcholine B. dopamine C. epinephrine D. norepinephrine 5. Somatic nerves send nerve impulses to (LO 5.1) A. smooth muscle B. skeletal muscle C. cardiac muscle D. visceral organs 6. During the fight or flight reaction, the adrenal medulla predominately releases (LO 5.4) A. acetylcholine B. norepinephrine C. epinephrine D. dopamine
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Which of the following belong in the CNS? (LO 5.1) A. spinal cord B. cranial nerves C. spinal nerves D. brain 2. Choose the body functions that occur during the fight or flight reaction. (LO 5.3) A. digestion B. urination C. elimination D. bronchoconstriction 3. Which of the following neurotransmitters work on the cholinergic nerves? (LO 5.5) A. norepinephrine B. epinephrine C. catecholamine D. acetylcholine
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Chapter Review Continued 4. Select the nerves that are part of the parasympathetic division of the nervous system. (LO 5.1) A. thoracic B. lumbar C. cranial D. sacral 5. What happens when the parasympathetic nervous system is activated? (LO 5.2) A. All nerves are activated. B. Specific nerves are stimulated. C. The whole body is stimulated. D. No nerves are activated.
Sequencing Place the following in order from first process to last process in vasoconstriction. (LO 5.2)
______________
______________
______________
First
______________ Last
vasoconstriction smooth muscle contraction strong sympathetic nerve firing increased blood pressure
Classification Classify the following as cranial or sacral parasympathetic nerves. (LO 5.2) oculomotor nerve
vagus nerve
pelvic nerves
glossopharyngeal nerves
hypogastric nerves Cranial
Sacral
Matching Match the following effects of nervous system activation with the correct division. (LO 5.4) a. parasympathetic b. sympathetic 1. 2. 3. 4. 5. 6. 7. 8.
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____ ____ ____ ____ ____ ____ ____ ____
increased GI motility urinary bladder relaxation increased heart rate pupil constriction urinary sphincter relaxation acetylcholine released vasoconstriction increased heart contractility
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Labeling Fill in the missing labels. (LO 5.2)
For interactive animations, videos, and assessment visit:
www.mcgrawhillconnect.com Chapter 5 • Chapter Review
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Chapter 6
Drugs Affecting the Sympathetic Nervous System DRUG CLASS AT A GLANCE OTC
EPINEPHRINE AEROSOL, DECONGESTANTS
PRESCRIPTION
YES
SCHEDULED DRUGS
NO
FDA PREGNANCY CATEGORY
B, C
INDICATIONS Cardiovascular and respiratory conditions Nasal and ocular congestion
KEY TERMS adrenergic neuronal blocker: drug that acts at the neuronal nerve endings to reduce the formation or release of NE. alpha-adrenergic drug: drug that stimulates the alpha adrenergic receptors. alpha-1 adrenergic blocker: drug that blocks the alpha-1 effects of NE and EPI. alpha-1 adrenergic receptor: receptor located on smooth muscle that mediates smooth muscle contraction. alpha-2 adrenergic receptor: receptor located on adrenergic nerve endings that reduces the release of NE. beta-1 adrenergic receptor: receptor located on the heart that increases heart rate and force of contraction. beta-2 adrenergic receptor: receptor located on smooth muscle that relaxes smooth muscle when stimulated. catecholamine: refers to norepinephrine, epinephrine, and other sympathomimetic compounds that possess the catechol structure. false transmitter: substance formed in nerve endings that mimics and interferes with the action of the normal neurotransmitter. nonselective beta-adrenergic blocker: drug that blocks both beta-1 and beta-2 adrenergic receptors.
nonselective beta-adrenergic drug: drug that stimulates both beta-1 and beta-2 receptors. selective beta-1 adrenergic blocker: drug that blocks only beta-1 receptors. selective beta-2 adrenergic drug: drug that stimulates only beta-2 receptors at therapeutic doses. sympatholytic: refers to the action of an adrenergic blocking drug or an action that decreases sympathetic activity. sympathomimetic: refers to the action of an adrenergic drug or an action that increases sympathetic activity.
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Learning Outcomes
After studying this chapter, you should be able to
6.5 describe the main pharmacological effects and uses of beta-adrenergic drugs.
6.1 explain how the adrenergic nerve endings function both to release and inactivate norepinephrine.
6.6 describe the clinical indications and adverse effects associated with alpha-blocking drugs.
6.2 list the different adrenergic receptors and describe the actions they mediate.
6.7 recognize the clinical indications and adverse effects associated with beta-blocking drugs.
6.3 explain the effects of norepinephrine (NE) and epinephrine (EPI) on alpha and beta receptors.
6.8 describe the mechanism of action of the adrenergic neuronal blocking drugs.
6.4 describe the main pharmacological effects and uses of alpha-adrenergic drugs.
Introduction
The sympathetic nervous system regulates the activity of the internal organs and glands when the body is expending energy during physical exertion and situations that are stressful or threatening to the body. Mental anguish, anxiety, physical trauma, and the discovery that one has developed a serious disease are examples of stressful conditions that activate the sympathetic nervous system. Peripheral sympathetic nerves, referred to as adrenergic nerves, release the neurotransmitter norepinephrine (NE). Norepinephrine binds to its adrenergic receptors and produces the effects that are associated with sympathetic stimulation. The adrenal medulla releases the hormone epinephrine (EPI), which travels in the blood and also stimulates the adrenergic receptors. EPI (adrenaline) is released from the adrenal medulla in larger amounts during stress and emergency situations (fight or flight reaction). Norepinephrine and epinephrine are chemically similar and are generally referred to as the catecholamines. The drugs used to affect sympathetic activity are classified as adrenergic drugs (agonists) that increase sympathetic activity and adrenergic blockers (antagonists) that decrease sympathetic activity. Adrenergic drugs are used to increase blood pressure, stimulate the heart, and produce bronchodilation. Adrenergic blockers are primarily used to lower blood pressure and reduce cardiac stimulation in conditions where there is excessive sympathetic activity.
LO 6.1
ADRENERGIC NERVE ENDINGS It is important to have an understanding of how the adrenergic nerve endings function. The nerve endings are mainly concerned with the formation of NE. The adrenergic nerve ending takes up the amino acid tyrosine and through a series of enzymatic steps forms dihydroxyphenylalanine (DOPA) and then dopamine (DA), which is converted into NE. Norepinephrine is then stored within vesicles inside the nerve endings. When the adrenergic nerves are stimulated, NE is released. Norepinephrine then travels across the synaptic cleft to the smooth or cardiac muscle membrane, attaches to adrenergic receptors, and produces the sympathetic response. Most of the NE then passes back into the nerve endings (reuptake).
Inside the nerve endings, the NE may be reused or may be destroyed by the enzyme monoamine oxidase (MAO). These actions are illustrated in Figure 6.1.
Norepinephrine versus Epinephrine Although NE and EPI are both adrenergic neurotransmitters, there are some important differences in the effects that each produces. Both NE and EPI stimulate many of the internal organs to increase sympathetic activity. EPI is only produced in the adrenal medulla. It is released into the bloodstream, where it acts as a hormone to stimulate all adrenergic receptors. One of the actions of EPI is to relax smooth muscle; NE does not relax smooth muscle. Relaxation of respiratory smooth Chapter 6 • Drugs Affecting the Sympathetic Nervous System
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Figure 6.1
Schematic Representation of Neurohumoral Transmission at Adrenergic Nerve Endings
Synaptic cleft
DOPA
DA
␣ -1
Tyr
Sympathetic effector organ
Response (contraction of smooth muscle)
1
NE Sympathetic postganglionic fiber
NE -1 ␣-2
Response (cardiac stimulation)
2
MAO
Inactive metabolites
3
Tyrosine (Tyr) is taken up into the nerve ending and enzymatically converted to dihydoxyphenylalanine (DOPA). DOPA is converted to dopamine (DA), which enters storage vesicles where it is synthesized and stored as norepinephrine (NE). Upon adrenergic stimulation, NE is released from the adrenergic nerve ending into the synaptic cleft. NE then can (1) stimulate adrenergic receptors on internal organs and glands, (2) stimulate alpha-2 receptors on the postganglionic nerve ending to inhibit further release of NE, and (3) undergo reuptake back into the nerve ending for restorage in vesicles or metabolism to inactive metabolites by MAO.
muscle by EPI promotes bronchodilation. This effect fits into the fight or flight reaction because more oxygen passes into the lungs when the respiratory tract is dilated. Because of the differences in the responses produced by NE and EPI, several different adrenergic receptor types have been identified. LO 6.2
ADRENERGIC RECEPTORS The two main adrenergic receptor types are classified as alpha- and beta-adrenergic receptors. Alpha receptors are divided into alpha-1 and alpha-2 receptor subtypes. The beta receptors are divided into beta-1 and beta-2 subtypes. Although some organs contain more than one type of receptor, one receptor type usually predominates and determines the overall response of the organ. Alpha-1 adrenergic receptors are found predominantly on smooth muscle membranes of arteries, veins, and sphincters of the urinary and gastrointestinal tract. When stimulated by NE or EPI, they produce contraction; for example, vasoconstriction of most blood vessels. Alpha-2 adrenergic receptors are located on adrenergic nerve endings; they are activated by NE and EPI to activate a negative feedback mechanism that reduces and 74
regulates the release of additional NE. Drugs that affect this receptor are used in the treatment of hypertension and are discussed in Chapter 26. Beta-adrenergic receptors are found on both cardiac and some smooth muscle membranes. In the heart, the predominant beta receptors are classified as beta-1 receptors, and when stimulated by NE or EPI, they increase heart rate and force of contraction. The predominant beta receptor in the smooth muscle of some organs and tissues is the beta-2 receptor. When these beta-2 receptors are stimulated by EPI, they produce vasodilation (mainly skeletal muscle blood vessels and coronary arteries) and bronchodilation (relaxation of bronchiolar smooth muscle). Note that alpha-receptor stimulation causes smooth muscle contraction at some organ sites while beta-2 receptor stimulation causes smooth muscle relaxation at other organ sites. Table 6:1 compares the effects of NE and EPI on the adrenergic receptors of several organs. Although the classification system for the adrenergic receptors seems confusing, it is useful for classifying drugs. There are two general terms used to categorize drugs that affect the sympathetic nervous system. Sympathomimetics are adrenergic drugs (alpha and beta agonists) that produce effects that are similar to stimulating or mimicking the sympathetic nervous system.
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LO 6.3
Table 6:1
Effects of Norepinephrine and Epinephrine on Alpha and Beta Receptors Receptor
Organ
Epinephrine effect
Norepinephrine effect
Alpha-1 (contraction of smooth muscle)
Most arteries and veins
Vasoconstriction
Vasoconstriction
Iris muscle (eye)
Contraction—pupillary dilation
Contraction—pupillary dilation
Alpha-2
Adrenergic nerve ending
Decrease release NE
Decrease release NE
Beta-1 (stimulation of cardiac muscle)
Heart
Greater increase in heart rate, force of contraction, and atrioventricular conduction
Moderate increase in heart rate, force of contraction, and atrioventricular conduction
Beta-2 (relaxation of smooth muscle)
Bronchiolar smooth muscle
Bronchodilation
Uterus
Relaxation
Norepinephrine does not stimulate beta-2 receptors
Skeletal muscle vessels and coronary artery vessels
Vasodilation
Sympatholytics refer to adrenergic blocking drugs (alpha, beta, and neuronal blockers) that antagonize or decrease sympathetic activity. Sympathomimetic drugs, including NE and EPI, that produce contraction of smooth muscle by stimulating the alpha-1 adrenergic receptors are referred to as alpha-adrenergic drugs. Drugs, including EPI, that both stimulate the heart (stimulate beta-1 receptors) and cause relaxation of smooth muscle (stimulate beta-2 receptors) are referred to as nonselective betaadrenergic drugs. EPI is one of the few substances that stimulates all alpha and beta receptors. There are also beta-adrenergic drugs that selectively stimulate only the beta-2 receptors at therapeutic doses. These drugs are referred to as the selective beta-2 adrenergic drugs and are used primarily as bronchodilators. Sympatholytic drugs that block the alpha effects of NE and EPI are known as the alpha-adrenergic blockers. Most alpha blockers available today only block the alpha-1 receptor (relaxation of smooth muscle). Drugs that block both the beta-1 and beta-2 effects of EPI are known as the nonselective beta-adrenergic blockers. Drugs that block only beta-1 receptors are known as selective beta-1 adrenergic blockers. The effect of these alpha- and beta-blockers is to decrease sympathetic activity, especially in the cardiovascular system. The blocking drug competes with NE or EPI for the receptor sites. When the blocking drug occupies the receptor, it prevents NE and EPI from producing an
effect. Another method to inhibit the sympathetic system is to decrease the formation or the release of NE from the adrenergic nerve ending. Drugs that act at the adrenergic nerve endings to reduce the formation or release of NE are known as the adrenergic neuronal blockers. Table 6:2 summarizes the adrenergic drug classes, receptor sites, and main drug effects. LO 6.4
ALPHA-ADRENERGIC DRUGS Norepinephrine is considered to be the parent or prototype drug for the alpha drug class. The alpha-adrenergic drugs have chemical structures and produce effects that are almost identical to those of NE. The most important clinical effect produced by the alpha-adrenergic drugs is stimulation of the alpha-1 receptors to cause contraction of smooth muscle. This includes vasoconstriction of most blood vessels, contraction of sphincter muscles in the gastrointestinal (inhibits movement of intestinal contents) and urinary (restricts passage of urine) tracts, and contraction of ocular muscles that causes dilation of the pupil of the eye (mydriasis). The actions on the sphincters of the GI and urinary tracts are not therapeutic and are usually side effects to the use of alpha drugs.
Clinical Indications Alpha drugs are administered intravenously in hypotensive states; for example, after surgery, to increase Chapter 6 • Drugs Affecting the Sympathetic Nervous System
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Table 6:2
Summary of Major Adrenergic Drug Classes and Receptor Sites Acted Upon Adrenergic drug class
Receptor site
Main drug effect
Alpha-1
Alpha-1 effect, contraction of alpha-1 mediated smooth muscle (vasoconstriction)
Alpha-2
Alpha-2 effect, negative feedback effect to decrease release of NE
Beta-1
Beta-1 effect, cardiac stimulation; increased heart rate and force of contraction
Beta-2
Beta-2 effect, relaxation of beta-2 mediated smooth muscle (bronchodilation)
Beta-2
Beta-2 effect, relaxation of beta-2 mediated smooth muscle (bronchodilation)
Selective alpha-1 blockers
Alpha-1
Alpha-1 blockade, relaxation of alpha-1 mediated smooth muscle (vasodilation)
Nonselective beta-blockers
Beta-1
Beta-1 blockade, decrease cardiac function; decrease heart rate, contraction
Beta-2
Beta-2 blockade, beta-2 mediated smooth muscle contraction (nontherapeutic)
Selective beta-1 blockers
Beta-1
Selective beta-1 blockade, decreases cardiac function (decrease heart rate, force of myocardial contraction)
Neuronal blockers
Adrenergic nerve ending
Interferes with synthesis and/or release of NE from nerve ending, decreases all sympathetic activity, lowers blood pressure and cardiac function
Sympathomimetics (Agonists) Alpha drugs
Nonselective beta drugs
Selective beta-2 drugs Sympatholytics (Antagonists)
Note to the Health Care Professional CAUT IO N During intravenous infusion of alphaadrenergic drugs, the IV needle should be checked frequently to make certain that the drug is not infiltrating the skin. Infiltration by alpha drugs causes intense vasoconstriction of skin blood vessels, which can lead to death of skin cells and gangrene.
blood pressure and maintain circulation. Vasoconstriction of blood vessels in mucous membranes of the nasal sinuses produces a decongestant effect. Consequently, some of these drugs are included in over-the-counter 76
(OTC) cold and allergy preparations for relief of nasal congestion. A few of the alpha drugs also are used in ophthalmology to dilate the pupils (mydriatic drugs) and as ocular decongestants. Table 6:3 lists the alpha drugs and their main uses.
Adverse Effects The major adverse effect of the alpha-adrenergic drugs administered by IV infusion is due to excessive vasoconstriction of blood vessels. This may result in increased blood pressure and hypertensive crisis. In some patients, this can lead to either hemorrhage (usually cerebral) or cardiac arrhythmias. Consequently, extreme caution must be observed with hypertensive or cardiac patients. Patients receiving parenteral administration of these drugs should have blood pressure recordings taken at frequent intervals. The most common side effect of decongestant use is irritation of the nasal sinuses or eyes due to excessive dryness caused by the vasoconstrictive decrease in blood flow.
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Table 6:3
Representative Alpha-Adrenergic Drugs Main use
Dosage forms
Metaraminol (Aramine)
Increase blood pressure
Parenteral injection on n
Midodrine (ProAmatine)
Increase blood pressure
Tablets
Norepinephrine (Levophed )
Increase blood pressure
Parenteral injection on
Phenylephrine (Neo-Synephrine)
Increase blood pressure
Parenteral injection on
Drug (Trade Name) Drugs used to treat hypotension
Drugs used for nasal and ocular decongestion Naphazoline (Privine) (Naphcon)
Nasal decongestant Ocular decongestant
Nasal solution, spray ray Ophthalmic solution, ion, drops
Phenylephrine (Neo-Synephrine)
Nasal decongestant
Nasal solution, spray ray
Pseudoephedrine (Sudafed)
Nasal decongestant
Tablets, capsules
Tetrahydrozoline (Tyzine) (Visine)
Nasal decongestant Ocular decongestant
Nasal solution, drops rops Ophthalmic solution, ion, drops
Xylometazoline (Otrivin)
Nasal decongestant
Nasal solution, spray ray
LO 6.5
BETA-ADRENERGIC DRUGS The beta-adrenergic drugs have a selective action to stimulate beta receptors. With the exception of NE and EPI, most beta drugs produce very few alpha effects.
Beta Drug Effects The most important actions of the beta drugs are stimulation of the heart (beta-1) and bronchodilation (beta-2). Isoproterenol is the most potent beta-adrenergic drug that produces both of these effects. This dual action (heart and respiratory passages) is the main disadvantage of isoproterenol in treating bronchoconstriction caused by asthma or allergy. With isoproterenol, there is often overstimulation of the heart along with the bronchodilator effect. For this reason, a search was conducted to discover beta drugs that would selectively stimulate only the beta-2 receptors without causing excessive stimulation of beta-1 receptors in the heart. Several of these selective beta-2 drugs were discovered and are now widely used as bronchodilators. The use of beta-adrenergic drugs is discussed in Chapter 32 with the treatment of asthma.
Beta-2 receptors are also found in uterine smooth muscle. Stimulation of beta-2 receptors within the uterus relaxes smooth muscle and inhibits uterine contractions, which can occur during premature labor. Selective beta-2 drugs such as terbutaline may be used to arrest premature labor. Table 6:4 lists the various beta drugs and their main clinical uses.
Clinical Indications for Epinephrine Epinephrine is the drug of choice for the immediate treatment of acute allergic reactions, such as anaphylaxis. Anaphylaxis can be caused by insect stings, drugs, or other allergens in sensitized individuals. There is difficulty in breathing, decreased blood pressure, and other symptoms of shock. In these situations, EPI (stimulates both alpha and beta receptors) administered by subcutaneous injection is the preferred treatment. For individuals who are susceptible to immediate-type (anaphylactic) allergic reactions, a preparation of epinephrine is available for immediate self-injection. EpiPen is designed as an auto-injector (EpiPen Auto-Injector) that delivers a Chapter 6 • Drugs Affecting the Sympathetic Nervous System
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Table 6:4
Beta-Adrenergic Drugs Drug (Trade Name)
Receptors
Main use
Dosage form
Dopamine (Intropin)
Alpha, beta-1
Circulatory shock
IV infusion
Ephedrine (generic)
Alpha, beta-1, beta-2
Bronchodilator
Capsules, parenteral
Epinephrine (Adrenaline) (EpiPen) (Primatene mist)
Alpha, beta-1, beta-2 Same as above Same as above
Acute allergy/asthma Acute allergy Bronchodilator
Parenteral SC injection Parenteral IM injection Aerosol inhalant
Isoproterenol (Isuprel )
Beta-1, beta-2
Bronchodilator
Nebulization
Albuterol (Proventil )
Beta-2
Bronchodilator
Aerosol inhalant, tablets, syrup
Dobutamine (Dobutrex)
Beta-1
Acute heart failure
IV infusion
Isoetharine (Bronkometer)
Beta-2
Bronchodilator
Nebulization
Levalbuterol (Xopenex)
Beta-2
Bronchodilator
Nebulization
Metaproterenol (Alupent)
Beta-2
Bronchodilator
Aerosol inhalant
Salmeterol (Serevent)
Beta-2
Bronchodilator
Aerosol inhalant
Terbutaline (Brethine)
Beta-2
Bronchodilator Preterm labor
Parenteral injection, tablets
Nonselective drugs
Selective drugs
fixed amount of epinephrine by intramuscular injection (Figure 6.2). EpiPen must be carried by the individual and administered immediately following the onset of an anaphylactic-type allergic reaction. The alpha actions of EPI also are used during surgical procedures or in combination with local anesthetics to produce vasoconstriction. The alpha effect decreases blood flow and bleeding, and prolongs the action of local anesthetics at the site of injection. The beta effects of EPI are useful for cardiac stimulation (beta-1) in emergencies (such as cardiac arrest) and for bronchodilation (beta-2) in the treatment of asthma. Epinephrine is available OTC for inhalation as an aerosol for the relief of acute bronchospasm, but it is not recommended for the chronic control of asthma because of cardiac stimulation. The routes of administration and durations of action of the bronchodilators are presented in Chapter 32.
Dopamine Dopamine functions as a neurotransmitter in the brain and also is formed as a precursor in the synthesis of NE in peripheral adrenergic nerve endings. When prepared as a drug and administered intravenously, dopamine produces several cardiovascular effects that are useful in the treatment of circulatory shock. 78
At low doses (0.5 to 2.0 mcg/kg/minute), dopamine stimulates dopaminergic receptors in renal and mesenteric blood vessels, resulting in vasodilation and increased renal blood flow. At moderate doses (2 to 10 mcg/kg/minute), dopamine also stimulates beta-1 receptors, which increases myocardial contractility and increases cardiac output. Increasing cardiac output and increasing renal blood flow are important actions during shock, when blood pressure and cardiac function are drastically reduced. At higher dosages, dopamine stimulates alpha receptors to produce vasoconstriction. Dopamine is administered by continuous IV infusion, and the effects disappear shortly after the infusion is stopped. Adverse effects from overdosage usually involve excessive stimulation of the heart and increased blood pressure (alpha effect). Dobutamine (Dobutrex) is a drug, similar to dopamine, that possesses greater beta-1 effects to increase myocardial contractility. The main use of dobutamine is in acute heart failure, where it is administered by IV infusion.
Adverse Effects The beta drugs may produce central nervous system (CNS) stimulation resulting in restlessness, tremors, or
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Figure 6.2 EpiPen Auto-Injector
Patient Administration and Monitoring Check vital signs (heart rate, blood pressure, respiration) frequently during parenteral administration of adrenergic drugs. Check to ensure that IV lines are properly adjusted and needles have not infiltrated. Observe for sympathetic signs of drug overdosage: sweating, trembling, chest pain, respiratory difficulty, significant increases in blood pressure. Instruct patient to report signs of trembling, sweating, chest pain, shortness of breath, heart irregularities, weakness, or feelings of faintness.
The EpiPen Auto-Injector is used for self intramuscular injection of epinephrine immediately after the beginning of an anaphylactic-type allergic reaction.
anxiety. The main adverse effect of the older beta drugs (EPI or isoproterenol) is overstimulation of the heart, which may result in palpitations or other cardiac arrhythmias. These drugs are used with extreme caution in patients with existing heart disease. Drugs that produce beta-2 effects dilate the blood vessels of skeletal muscle. This dilation may lower blood pressure but rarely results in hypotension. At higher than therapeutic doses, the selective beta-2 drugs also can begin to stimulate cardiac beta-1 receptors, which may cause overstimulation of the heart. Use of beta-2 drugs to arrest preterm labor can cause a variety of cardiovascular effects and complications. Fetal heart rate and maternal pulse rate and blood pressure should be closely monitored.
skin and extremities) such as Raynaud’s disease, where the vasodilation increases blood flow to the skin and extremities. Alpha-blockers are used in the treatment of pheochromocytoma, a tumor of the adrenal medulla where excessive catecholamine levels cause severe hypertension. Phenoxybenzamine, which has a long duration of action, is used to lower and control blood pressure until surgery to remove the tumor can be performed. In benign prostatic hyperplasia (males), there is enlargement of the prostate gland, which interferes with urine flow through the ureter. Alpha-blocking drugs relax the smooth muscle of the ureter, which improves urinary flow. Table 6:5 lists the alpha-blockers and their main uses.
Adverse Effects LO 6.6
ALPHA-ADRENERGIC BLOCKING DRUGS The alpha-blockers compete with NE and EPI for binding to the alpha-adrenergic receptors. When the alphablocker binds to the receptors, it prevents NE and EPI from producing the alpha sympathetic responses. Consequently, normal sympathetic activity is decreased in organs that have alpha receptors. The main pharmacologic effect of alpha-blockers is to cause relaxation of smooth muscle.
Clinical Indications The alpha-blockers are used in the treatment of hypertension, especially when excessive vasoconstriction is present. The treatment of hypertension is discussed in Chapter 26. The alpha-blockers are also used in peripheral vascular conditions (poor blood flow to
Whenever the activity of one division of the autonomic nervous system is blocked (sympathetic), activity in the other division (parasympathetic) appears to increase. After alpha blockade, when sympathetic activity is blocked, the side effects are similar to an increase in parasympathetic activity in the organs that are blocked. You should note this generalization, that blocking one division of the ANS usually produces some effects that are similar to stimulating the other division. Constriction of the pupils (miosis), nasal congestion, and increased GI activity may be experienced after alpha blockade. Compensatory reflex tachycardia also occurs if the blood pressure is significantly lowered. In addition, the alpha-blockers interfere with normal cardiovascular reflexes that control blood pressure. Consequently, some patients experience orthostatic hypotension and fainting, especially when first starting therapy. Patients should be advised to exercise caution when changing positions from lying or sitting to standing. Chapter 6 • Drugs Affecting the Sympathetic Nervous System
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Table 6:5
Alpha-Adrenergic Blocking Drugs Drug (Trade Name)
Main use
Common daily dosage range
Alfuzosin (Uroxatral)
Treatment of benign prostatic hyperplasia
10 mg PO
Doxazosin (Cardura)
Treatment of hypertension Treatment of benign prostatic hyperplasia
1–16 mg PO 1–8 mg PO
Phenoxybenzamine (Dibenzyline)
Treatment of pheochromocytoma
50–300 mg PO
Prazosin (Minipress)
Treatment of hypertension
1–20 mg PO
Tamsulosin (Flomax)
Treatment of benign prostatic hyperplasia
0.4–0.8 mg PO
Terazosin (Hytrin)
Treatment of hypertension Treatment of benign prostatic hyperplasia
1–5 mg PO 1–10 mg PO
LO 6.7
BETA-ADRENERGIC BLOCKING DRUGS Beta-blocking drugs bind to beta-adrenergic receptors and antagonize the beta effects of EPI and NE. Patients with hypertension, angina pectoris, and cardiac arrhythmias often have increased sympathetic activity, with excessive amounts of EPI and NE being released. By occupying beta receptors, the beta-blockers antagonize and reduce the effects of EPI and NE on beta receptors. The heart (beta-1) is one of the most important beta organs and the main clinical use of beta-blockers is to decrease the activity of the heart. Blockade of the beta-1 receptors produces a decrease in heart rate, force of contraction, and impulse conduction through the conduction system of the heart. These effects are useful in patients with fast heart rates (tachycardia), cardiac arrhythmias, and other cardiac conditions where excessive sympathetic activity is present. Decreasing cardiac function also decreases blood pressure and beta-blockers are used in the treatment of hypertension. There are no specific therapeutic indications for blocking the beta-2 receptors.
Types of Beta-Blockers The beta-blockers are divided into the nonselective betablockers (block both beta-1 and beta-2 receptors) and the selective beta-1 blockers. At therapeutic doses, the selective beta-blockers block only beta-1 receptors. At higher doses, the selective beta-blockers also may begin to block beta-2 receptors. Propranolol was the first betablocker used clinically; it blocks both beta-1 and beta-2 80
receptors. The other nonselective beta-blockers produce similar effects, except for labetalol, which also blocks alpha-1 receptors. The major pharmacokinetic differences among these drugs are the duration of action and the extent of drug metabolism. Table 6:6 lists the betablockers and their main indications.
Pharmacologic Effects The main effects produced by propranolol are a decrease in rate, force of contraction, and conduction velocity of the heart. In addition, there is usually a lowering of blood pressure. Reducing the effort and work of the heart causes a decrease in oxygen consumption. This effect is beneficial in the treatment of various cardiovascular conditions such as angina pectoris, especially when there is hyperactivity of the sympathetic nervous system. Propranolol is administered either orally or intravenously. After oral administration, the drug is carried directly to the liver by the portal system. With propranolol, there is significant metabolism on the first passage through the liver (first-pass metabolism), which reduces the amount of drug that eventually reaches the systemic circulation. Beta-blockers also affect carbohydrate and lipid metabolism. Interference with carbohydrate metabolism is usually insignificant; however, diabetic patients may experience hypoglycemia. Serum lipid levels (triglycerides) may be increased by continuous therapy with these drugs. Propranolol is the most lipid-soluble beta-blocker and passes into the brain, where it can exert pharmacological effects. These effects include CNS sedation, depression, and decreased central sympathetic activity,
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Table 6:6
Beta-Adrenergic Blocking Drugs Main indications
Common daily dosage range
Carvedilol (Coreg)
Hypertension Chronic heart failure
12.5–50 mg PO 6.25–100 mg PO
Labetalol (Normodyne)
Hypertension
200–800 mg PO
Nadolol (Corgard)
Hypertension, angina pectoris
80–240 mg PO
Pindolol (Visken)
Hypertension
10–60 mg PO
Propranolol (Inderal )
Hypertension, migraine Angina pectoris Arrhythmias Life-threatening arrhythmias Post-myocardial infarction
80–240 mg PO 80–320 mg PO 40–120 mg PO 1–3 mg IV 180–240 mg PO
Timolol (Blocadren, Timoptic)
Hypertension, post-myocardial infarction Glaucoma
20–40 mg PO
Acebutolol (Sectral )
Hypertension Ventricular arrhythmias
400–800 mg PO 400–1200 mg PO
Atenolol (Tenormin)
Hypertension, angina pectoris
50–100 mg PO
Bisoprolol (Zebeta)
Hypertension, chronic heart failure
5–20 mg PO
Esmolol (Brevibloc)
Supraventricular tachycardia
IV infusion (dose variable)
Metoprolol (Lopressor)
Hypertension, angina pectoris, chronic heart failure
100–400 mg PO
Drug (Trade Name) Nonselective blockers
Topical drops
Selective beta-1 blockers
which may contribute to the lowering of blood pressure in the treatment of hypertension. Nadolol and atenolol are lipid-insoluble (water-soluble) beta-blockers, which do not pass into the brain and are excreted mostly unmetabolized in the urine.
Clinical Indications Propranolol and other beta-blockers are used in the treatment of angina pectoris (Chapter 24), hypertension (Chapter 26), and various cardiac arrhythmias (Chapter 23). Beta-blockers also are one of the drug classes used in the treatment of chronic heart failure (Chapter 22), where decreasing excessive sympathetic activity slows the heart rate and appears to decrease the risk of sudden death. Other uses include the treatment of
glaucoma, where beta-blockers decrease intraocular pressure; treatment of migraine headaches, where they often reduce the number of migraine attacks; and after myocardial infarction, where with chronic therapy betablockers appear to decrease the incidence of additional myocardial infarction and sudden cardiac death. Esmolol is a short-acting drug that is administered intravenously in emergency situations. It has a quick onset of action to lower ventricular heart rate in cases of supraventricular tachycardia. The half-life of esmolol is about 10 minutes.
Adverse Effects Common side effects of beta-blockers include nausea and diarrhea. More serious adverse effects occur when heart Chapter 6 • Drugs Affecting the Sympathetic Nervous System
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function is excessively reduced. This reduction usually produces bradycardia and may lead to congestive heart failure or cardiac arrest. In general, propranolol and nonselective beta-blockers should not be used in patients with asthma or other respiratory conditions. By blocking beta-2 receptor sites, nonselective beta-blockers may cause bronchoconstriction in individuals with asthma or other respiratory conditions. This bronchoconstriction may precipitate a respiratory emergency. The selective beta-1 blockers have less of a tendency to do this. However, at higher than therapeutic doses, they also may begin to block beta-2 receptors and cause bronchoconstriction. Beta-blockers that gain access to the brain like propranolol may cause drowsiness, mental depression, and other CNS disturbances.
Drug Interactions The most serious drug interactions involve therapy of betablockers with other drugs that decrease cardiovascular function. These include cardiac glycosides, antiarrhthymic drugs, and calcium blockers. These drug interactions usually lower heart rate and cardiac output, which can lead to hypotension and drug-induced heart failure. LO 6.8
ADREN ADRENERGIC NEURONAL BLOCKING DRUGS The main activity that occurs inside the adrenergic nerve endings is the formation and storage of NE. Norepinephrine is synthesized from amino acids, either phenylalanine or tyrosine. Several drugs interfere with the formation or the storage of NE. Such drugs are called
Patient Administration and Monitoring Check vital signs frequently with parenteral drug administration. Observe patient frequently for signs of cardiac depression (beta-blockers) and hypotension (alpha- and beta-blockers). Explain to patient the common drug side effects: weakness, fatigue, dizziness, and sedation. Instruct patient to report slow pulse rate, chest pain, respiratory difficulties, mental confusion, nightmares, or impotency. Diabetic patients should be warned that beta-blockers may affect insulin and blood glucose levels, and that they should report any changes.
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adrenergic neuronal blockers. Figure 6.3 illustrates the sites of action of the neuronal blocking drugs.
Methyldopa (Aldomet) Methyldopa (alpha-methyldopa) interferes with the synthesis of NE in the nerve endings and greatly reduces the amount of NE that is formed. Consequently, less NE is released, and the activity of the sympathetic system is decreased. The adrenergic nerve ending also converts methyldopa into alpha-methylnorepinephrine, which is stored and released by the nerve endings like NE. The term false transmitter is used to describe drugs that produce neurotransmitter-like substances but reduce neuronal activity. The main use of methyldopa is in the treatment of hypertension to lower blood pressure. The most important site of action of methyldopa to reduce blood pressure is in the vasomotor center of the medulla oblongata (central effect). In the medulla, the formation and release of alpha-methylnorepinephrine activates alpha-2 receptors and leads to a decrease in sympathetic activity to vascular smooth muscle, which produces vasodilation and a lowering of blood pressure. The usual oral dose is 250 to 2000 mg/day (divided doses). During initial treatment with methyldopa, many patients experience drowsiness and/or sedation, but these effects tend to disappear as drug treatment continues. Other side effects include nausea, vomiting, diarrhea, nasal congestion, and bradycardia. In some patients, adverse reaction may cause one or more of the following: drug fever, liver dysfunction, hemolytic anemia, or a lupus-like syndrome resulting in skin eruptions and symptoms of arthritis.
Reserpine Reserpine is obtained from a plant, Rauwolfia serpentina, found mainly in India. The site of action of reserpine is the adrenergic nerve endings. Within the nerve endings, reserpine prevents the storage of NE inside the storage granules. Consequently, the adrenergic nerve endings are depleted of NE. When this occurs, the level of sympathetic activity is greatly reduced. By reducing sympathetic activity, reserpine produces vasodilation and a lowering of blood pressure. Reserpine is rarely used today because of its numerous adverse effects. In addition to its antihypertensive effect, reserpine produces CNS sedation and tranquilization. Before the introduction of the modern antipsychotic drugs, reserpine was widely used to treat psychoses. Most of the side effects of reserpine are caused by the decreased sympathetic activity. Side effects are similar to parasympathetic stimulation and include increased salivation, diarrhea, nasal congestion, bradycardia, and
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Figure 6.3
1
Sites of Action of Adrenergic Neuronal Blocking Drugs
a-MDA is converted into a-MNE
Alpha-methyldopa inhibits enzyme and is also converted into a-MDA
a-MDA DOPA
DA
Adrenergic receptors
a-MNE (false transmitter)
a-MNE
R NE
R
Sympathetic effector organ
(Normal pathway for synthesis of NE) NE Tyrosine Adrenergic nerve ending
MAO
Inactive metabolites
NE
2 Reserpine depletes vesicle of NE
3 Guanethidine prevents release of NE and depletes vesicles of NE
(1) Alpha-methyldopa inhibits the enzyme that normally converts DOPA to DA. In the process, DOPA is converted into alpha-methyldopamine (alpha-MDA) and then into the false transmitter alpha-methylnorepinephrine (alpha-MNE). (2) Reserpine depletes the nerve ending vesicles of NE, which is then metabolized by MAO to inactive metabolites. (3) Guanethidine acts on the nerve ending to block the release of NE and also depletes vesicles of NE, which is metabolized by MAO.
excessive hypotension. In the CNS, reserpine may produce excessive sedation, psychic disturbances such as confusion and hallucinations, or mental depression.
Preferred Treatment for Selected Conditions
Guanethidine (Ismelin)
The drug of choice for treating acute allergic reactions caused by insect stings, drugs, or other allergies is epinephrine, administered by subcutaneous injection. Selfinjectable preparations (EpiPen) are available and must be carried and administered as soon as possible. In addition, corticosteroids (Chapter 36) and antihistamines (Chapter 31) also can be administered but require time before the onset of action. Other supportive measures such as oxygen and IV fluids also may be required.
Guanethidine is a potent adrenergic neuronal blocker. There are two main actions that guanethidine exerts on the nerve endings. First, guanethidine prevents the release of NE from the nerve endings, and, second, guanethidine depletes the NE storage granules similarly to reserpine. These two effects produce a significant reduction of sympathetic activity. The main clinical use of guanethidine is to treat severe hypertension; the usual oral dose is 25 to 300 mg/day. The half-life of guanethidine is relatively long. Therefore, the effects of guanethidine continue for several days after drug treatment is terminated. The main adverse effects of guanethidine are caused by the decreased sympathetic activity and include diarrhea, nasal congestion, bradycardia, orthostatic hypotension, and impotency in males.
Guanadrel (Hylorel) Guanadrel produces effects similar to those produced by guanethidine. It is used in the treatment of hypertension and generally produces a lower incidence of adverse effects than does guanethidine.
Acute Allergic Reactions/Anaphylaxis
Benign Prostatic Hyperplasia Alpha-blockers such as tamsulosin (Flomax) and alfuzosin (Uroxatral ) are generally preferred to increase urine flow. In addition, finasteride (Proscar) and dutasteride (Avodart) are steroid inhibitors that block conversion of male testosterone to its active form and cause some reduction in the size of the prostate gland.
Bronchodilation The selective beta-2 drugs such as albuterol (Proventil ) or terbutaline (Brethine) with durations of action of 4–6 hours are usually the preferred drugs used to treat mild to moderate asthma. If longer-acting drugs are required, formoterol (Foradil ) and salmeterol (Serevent) may be Chapter 6 • Drugs Affecting the Sympathetic Nervous System
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Summary of Sites of Action for Adrenergic Drugs
indicated. Preparations that combine either formoterol or salmeterol with antiiflammatory corticosteroids are available and indicated for moderate to severe asthma. Bronchodilators and the treatment of asthma are more extensively discussed in Chapter 32.
Figure 6.4 provides a diagrammatic summary of typical adrenergic nerve fibers, adrenergic receptors, and representative drugs that act on each receptor site. In addition, Table 6:7 summarizes the major sympathetic drug classifications and receptor site terminology with drug examples. It is hoped that the summary figure and table will help clear up some of the confusion that always occurs when first encountering the autonomic nervous system.
Hypertension Alpha-blocking, beta-blocking, and adrenergic neuronal blocking drugs are all used in the treatment of hypertension. In addition, there are several other drug classes effective for hypertension; a discussion of hypertension and the antihypertensive drugs is presented in Chapter 26.
Figure 6.4
Diagrammatic Summary of Adrenergic Receptor Sites and Sites of Action of Adrenergic Drugs and Adrenergic Blocking Drugs. Alpha Drugs Norepinephrine Epinephrine Phenylephrine
Contraction of smooth muscle in tissues possessing alpha-1 receptors; e.g., vasoconstriction
␣ Alpha-Blocking Drugs Prazosin Relaxation of smooth muscle in Terazosin tissues possessing alpha-1 Doxazosin receptors; e.g., vasodilation ACH
Postganglionic nerve fiber
NE Selective Beta-1 Blockers Metoprolol Atenolol Esmolol (decrease heart rate and force of contraction)
Adrenergic Neuronal Blockers Methyldopa Reserpine Guanethidine Guanadrel (decrease sythesis and release of NE)
1 ACH
Nonselective Beta Drugs Epinephrine Beta-1 — Cardiac stimulation Isoproterenol Beta-2 — Relaxation of smooth Dopamine muscle; e.g., bronchodilation Dobutamine
NE 2
Nonselective Beta Blockers Beta-1 — Decrease heart rate, Propranolol force of contraction Nadolol Beta-2 — Blockade of beta-2 Pindolol receptors not clinically useful Selective Beta-2 Drugs Terbutaline Beta-2 — Relaxation of smooth muscle in tissues possessing beta-2 Albuterol receptors, bronchioles, uterus Fenoterol
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Table 6:7
Summary of Sympathetic Drug Classification and Receptor Site Terminology Site of action
/
Main effect
Drugs
Alpha-adrenergic drugs
Alpha-1 receptor
/
Smooth muscle contraction, vasoconstriction
NE, EPI, metaraminol, phenylephrine
Nonselective beta-1 & -2 adrenergic drugs
Beta-1 and beta2 receptors
/
Cardiac stimulation, smooth muscle relaxation, bronchodilation
EPI, isoproterenol
Selective beta-2 adrenergic drugs
Beta-2 receptors
/
Smooth muscle relaxation, bronchodilation
Albuterol, formoterol, salmeterol, terbutaline
Alpha-1 adrenergic blockers
Alpha-1 receptor
/
Smooth muscle relaxation, vasodilation
Doxazosin, prazosin, tamsulosin, terazosin
Nonselective beta-1 & -2 adrenergic blockers
Beta-1 and beta2 receptors
/
Cardiac depression, smooth muscle contraction (beta-2 organs)
Nadolol, pindolol, propranolol, timolol
Selective beta-1 adrenergic blockers
Beta-1 receptors
/
Cardiac depression (decrease HR/force of contraction)
Atenolol, acebutolol, esmolol, metoprolol
Adrenergic neuronal blockers
Adrenergic nerve ending
/
Decrease sympathetic activity
Guanadrel, guanethidine, methyldopa, reserpine
Drug classification Sympathomimetics (Agonists)
Sympatholytics (Antagonists)
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Chapter Review Understanding Terminology Match the definition or description in the left column with the appropriate terms in the right column. (LO 6.1, 6.2, 6.3) ___ 1.
Drug that blocks or decreases sympathetic nervous system activity.
___ 2. Drug that acts at the neuronal endings to reduce the formation or release of NE. ___ 3. Receptor that mediates smooth muscle contraction. ___ 4. Adrenergic receptor located on either the heart or smooth muscle. ___ 5. Drug that blocks both beta-1 and beta-2 effects of EPI. ___ 6. Drug that blocks the alpha effects of NE and EPI. ___ 7.
Chemical classification of norepinephrine and epinephrine.
a. adrenergic neuronal blocker b. alpha-blocker c. alpha receptor d. beta receptor e. catecholamine f. epinephrine g. nonselective beta-blocker h. sympatholytic i. sympathomimetic
___ 8. Adrenergic drug or effect that increases sympathetic nervous system activity. ___ 9. Hormone released from the adrenal medulla that stimulates the sympathetic nervous system.
Acquiring Knowledge Answer the following questions. 1. What is the main function of the sympathetic nervous system? (LO 6.1) 2. List the different types of adrenergic receptors and relate them to specific organ functions. (LO 6.2) 3. What two neurotransmitter substances are associated with the sympathetic nervous system? Describe the effects of each. (LO 6.1) 4. A patient brought into the emergency room is experiencing severe hypotension. Blood pressure reads 90/50. What class of drugs is indicated for treatment? What precautions should be observed when these drugs are administered? What would be the first indication that too much drug has been administered? (LO 6.4) 5. Following cardiac surgery, a patient suddenly experiences a drop in cardiac function and blood pressure. The patient may be developing heart failure. What drugs would most likely be indicated in this situation? What autonomic receptor, in particular, needs to be acted upon? Should it be stimulated or blocked? (LO 6.5) 6. Alpha- and beta-blockers are both indicated for the treatment of hypertension. Explain the difference in the mechanism of action of these two drug classes to lower blood pressure. (LO 6.6, 6.7)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. Following emergency administration of epinephrine subcutaneously (SQ) for an acute asthmatic attack, the physician prescribes terbutalin (Brethine) tablets three times daily. How is this drug classified? What is it supposed to do? What are its advantages over epinephrine in the treatment of chronic asthma? (LO 6.5) 2. One of your coworkers has been taking propranolol (Inderal ) regularly for a fast heart rate (tachycardia). Recently she has been complaining of tiredness and a feeling that she might faint. Is this effect drug related and if so, what is occurring? What advice might you give her? (LO 6.7)
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3. Assume that your employer, a busy physician, has asked you to help screen patients for potential prescription drug problems. Patient X visited the doctor’s office today complaining of “sinus”—sinus congestion, pressure, and headache. The doctor diagnosed an upper respiratory virus and prescribed phenylephrine for the sinus congestion and discomfort. You study Patient X’s chart and note that he has a history of hypertension. What should you advise the doctor about the drug she has prescribed for Patient X? (LO 6.4) 4. Betty has asthma and diabetes. She also has developed high blood pressure, for which her doctor just prescribed the drug propranolol. One of your duties as physician’s assistant is to make sure patients are not prescribed drugs that are contraindicated because of other health problems. What should you tell the doctor about Betty’s prescription for propranolol? (LO 6.7) 5. Linda is a 24-year-old with bronchial asthma that is well controlled. She is in her 26th week of pregnancy and is experiencing preterm labor. Using the PDR ® or F&C, determine whether ritodrine or terbutaline would be indicated to arrest her preterm labor. (LO 6.5) 6. Bill is a 38-year-old with a history of duodenal ulcers. He is currently maintained on cimetadine 800 mg HS. Today he was diagnosed with hypertension and his physician wants to initiate treatment with Lopressor. What dosing considerations should be made, if any? (LO 6.7)
Multiple Choice Use your critical-thinking skills to answer the following questions. 1. The main pharmacologic effect of norepinephrine on alpha-1 receptors is (LO 6.2) A. increased heart rate B. bronchodilation C. vasocontriction D. contraction of urinary bladder 2. The pharmacologic effect of IV metaraminol is (LO 6.4) A. vasodilation B. vasoconstriction C. cardiac stimulation D. cardiac depression 3. Epinephrine stimulates (LO 6.2) A. alpha receptors B. beta-1 receptors C. beta-2 receptors D. all of the above 4. At therapeutic doses, albuterol stimulates (LO 6.5) A. alpha receptors B. beta-1 receptors C. beta-2 receptors D. all of the above 5. Tamsulosin is indicated for treatment of (LO 6.6) A. hypertension B. benign prostatic hyperplasia C. slow heart rate D. cardiac arrhythmias
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Chapter Review Continued 6. Metoprolol is classified as a(n) (LO 6.7) A. alpha-blocker B. nonselective beta-blocker C. selective beta-1 blocker D. adrenergic neuronal blocker 7. The mechanism of action of guanethidine is (LO 6.8) A. increased release of NE from adrenergic nerve ending B. decreased release of NE from adrenergic nerve ending C. blockade of all adrenergic receptors D. formation of a false transmitter in adrenergic nerve ending 8. The drug of choice to treat acute allergic reactions is (LO 6.4, 6.5) A. norepinephrine B. phenylephrine C. pseudoephedrine D. epinephrine
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Select all of the processes that occur with stimulation of a beta receptor. (LO 6.2) A. decreases artery constriction B. increases heart rate C. relaxes smooth muscle D. dilation of pupils 2. Norepinephrine works on the following receptors. (LO 6.3) A. Alpha-1 B. Alpha-2 C. Beta-1 D. Beta-2 3. Which of the following are actions of beta-adrenergic blocking drugs? (LO 6.7) A. decreasing heart activity B. preventing NE from working C. vasodilation D. lowering of blood pressure 4. Select the mechanisms by which reserpine works. (LO 6.8) A. blocks the NE receptor B. produces neurotransmitter-like substances C. interferes with synthesis of NE D. prevents storage of NE 5. Select the effects of EPI on the body. (LO 6.3) A. bronchodilation B. vasoconstriction C. relaxation of uterus D. increased heart conduction
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Sequencing Place the following in reverse order of occurrence in the nerve ending. (LO 6.1)
______________
______________
______________
______________
Last
First
NE reuptake NE released NE stored in nerve endings NE travels to smooth muscle
Documentation Using the prescription below, answer the following questions. (LO 6.6) a. b. c. d.
What is the brand name of the drug prescribed? What is the drug classification for this particular drug? In this dose, what is most likely being treated? List all applicable routes of administration.
Falls Clinic Practice RX 1000 River Avenue Anytown, USA 12345 931-555-1000 NAME:
Bob Cross
DATE:
ADDRESS: RX
terazosin
Sig:
10mg once daily
Dr. G. Scott Substitution Permitted DEA #:
#30
M.D.
M.D. Dispense as written REFILL:
NR
1
2
3
4
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Chapter Review Continued Labeling Fill in the missing labels. (LO 6.4, 6.5, 6.6, 6.7)
Norepinephrine Epinephrine Phenylephrine
Contraction of smooth muscle in tissues possessing alpha-1 receptors; e.g., vasoconstriction
a
Prazosin Terazosin Doxazosin
Spinal cord
ACH
Postganglionic nerve fiber
Relaxation of smooth muscle in tissues possessing alpha-1 receptors; e.g., vasodilation
Metoprolol Atenolol Esmolol (decrease heart rate and force of contraction)
NE
Methyldopa Reserpine Guanethidine Guanadrel (decrease sythesis and release of NE)
Epinephrine Isoproterenol Dopamine Dobutamine
Beta-1 — Cardiac stimulation Beta-2 — Relaxation of smooth muscle; e.g., bronchodilation
b1 ACH
NE b2 Propranolol Nadolol Pindolol
Beta-1 — Decrease heart rate, force of contraction Beta-2 — Blockade of beta-2 receptors not clinically useful
Terbutaline Albuterol Fenoterol
Beta-2 — Relaxation of smooth muscle in tissues possessing beta-2 receptors, bronchioles, uterus
For interactive animations, videos, and assessment visit:
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Chapter 7
Drugs Affecting the Parasympathetic Nervous System DRUG CLASS AT A GLANCE
KEY TERMS acetylcholinesterase: an enzyme that inactivates acetylcholine.
OTC
NO
PRESCRIPTION
YES
SCHEDULED DRUGS
NO
FDA PREGNANCY CATEGORY
B, C
INDICATIONS Alzheimer’s disease, g laucoma, myasthenia gravis, intestinal and urinary problems
anticholinergic: refers to drugs or effects that reduce the activity of the parasympathetic nervous system. cholinergic: refers to the nerves and receptors of the parasympathetic nervous system; also refers to the drugs that stimulate this system. muscarinic receptor: an older but more specific term for the cholinergic receptor on smooth and cardiac muscle. nicotinic-muscle (Nm) receptor: cholinergic receptor located at the neuromuscular junction of skeletal muscle. nicotinic-neural (Nn) receptor: cholinergic receptor located on both sympathetic and parasympathetic ganglia. parasympatholytic: refers to drugs (anticholinergic) that decrease activity of the parasympathetic nervous system. parasympathomimetic: refers to drugs (cholinergic) that mimic stimulation of the parasympathetic nervous system.
Learning Outcomes
After studying this chapter, you should be able to
7.4 list and briefly describe the clinical indications for the indirect-acting anticholinesterase drugs.
7.1 describe the neuronal release and inactivation of acetylcholine.
7.5 describe the pharmacologic actions, uses, and adverse effects of anticholinergic drugs.
7.2 list the three types of cholinergic receptors and the tissues where they are located.
7.6 list the preferred drug treatment for the most common conditions affected by parasympathetic activity.
7.3 compare the pharmacologic actions and uses of the direct-acting and indirect-acting cholinergic drugs.
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Introduction
The autonomic nervous system regulates the functions of the internal organs and glands. As previously discussed, the sympathetic division controls activity during physical exertion and stress (fight or flight). The parasympathetic division regulates body functions mainly during rest, digestion, and waste elimination. Parasympathetic stimulation increases the activity of the gastrointestinal and genitourinary systems and decreases the activity of the cardiovascular system. Drugs that increase parasympathetic activity (cholinergic) are used in the treatment of Alzheimer’s disease, glaucoma, myasthenia gravis, and urinary and intestinal stasis. Drugs that decrease parasympathetic activity (anticholinergics) are indicated for the treatment of overactive urinary and intestinal conditions, asthma and COPD, motion sickness, and during various ophthalmic procedures.
LO 7.1
CHOLINERGIC NERVE ACTIVITY The neurotransmitter of the parasympathetic system is acetylcholine (ACH). Nerves that release ACH are called cholinergic nerves; receptors that respond to cholinergic stimulation are called cholinergic receptors. However, as previously discussed (Chapter 5), cholinergic receptors are more specifically classified as either muscarinic or nicotinic depending on their location (see below). Drugs that stimulate muscarinic receptors located on smooth and cardiac muscle that produce effects similar to those of ACH are more commonly referred to as cholinergic. Drugs that block muscarinic receptors are referred to as anticholinergic. The anticholinergic drugs prevent ACH from acting upon its receptors. Drugs that affect the other cholinergic receptors, nicotinic-neural (Nn) and nicotinic-muscle (Nm), have different terminology and are presented in Chapters 8 and 9, respectively. Within the cholinergic nerve ending, acetylcholine is synthesized from a dietary substance, choline, and acetyl coenzyme A. ACH is then stored in vesicles until released by nerve stimulation. When a nerve is stimulated, ACH is released from its storage vesicles, travels across the synapse to the smooth or cardiac muscle membrane, and binds to the cholinergic receptors. The binding of ACH to the receptors initiates the changes that result in parasympathetic stimulation. In the area of the cholinergic receptors is an enzyme, acetylcholinesterase. Acetylcholinesterase inactivates ACH only when it is outside a nerve ending and not on the receptor. There is also an acetylcholinesterase enzyme, referred to as pseudocholinesterase, located in the liver and plasma that also can hydrolyze ACH and related drugs. Inactivation of ACH occurs quickly so that the effects of ACH last for only a few seconds. The toxins of certain bacteria can cause food poisoning, referred to as botulism. Some of these toxins can 92
inhibit the release of ACH from the cholinergic nerve ending to produce a flaccid type of skeletal muscle paralysis. In recent years, preparations of these toxins (Botox) have been injected into skeletal muscle to produce temporary paralysis in a variety of conditions (see below). Figure 7.1 illustrates the synthesis, storage, release, and inactivation of ACH that occurs at the cholinergic nerve ending. LO 7.2
CHOLINERGIC RECEPTORS Three types of cholinergic receptors are in the peripheral nervous system. Acetylcholine is the neurotransmitter for each receptor site. However, each of the cholinergic receptor types—muscarinic, nicotinic-neural (Nn), and nicotinic-muscle (Nm)—is blocked by a different drug class. There are three distinct classes of cholinergic blocking drugs, one for each type of receptor. Although the terminology used for the cholinergic receptors is confusing to beginning students, learning the terminology is essential for understanding the mechanism of drug action.
Muscarinic Receptors The cholinergic receptors at the parasympathetic postganglionic nerve endings (as shown in Figure 7.2(a)) are known as muscarinic receptors. The term muscarinic is derived from the drug muscarine, which is an alkaloid obtained from a particular type of mushroom. One of the first drugs used to establish the function of the autonomic nervous system (ANS), muscarine produces effects that are similar to those of ACH, but only at these particular receptor sites. Consequently, early pharmacologists referred to these receptors as muscarinic, and the terminology is still in use. Drugs that act like ACH
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Schematic Representation of Neurohumoral Transmission at Cholinergic Nerve Endings
Figure 7.1
Cholinergic nerve ending
Effector organs
ACH
Acetyl-CoA Choline
M
Response (muscarinic receptor on internal organs and glands)
N
Response (Nn at autonomic ganglia, Nm at skeletal muscle)
ACH
Choline ACH is inactivated enzymatically by acetylcholinesterase
Choline Acetate
Choline is taken up into the nerve ending and combined with acetyl-CoA to form acetylcholine (ACH). ACH is stored in vesicles and upon stimulation is released into the synaptic cleft to stimulate muscarinic receptors (M) on internal organs and glands, nicotinic receptors (Nn) on autonomic ganglia, and nicotinic receptors (Nm) on skeletal muscle. ACH is inactivated enzymatically by acetylcholinesterase.
Figure 7.2
The Cholinergic Sites of Drug Action and Their Associated Receptors
ACH
Muscarinic receptors
(a)
Parasympathetic neuron
ACH Muscarinic receptors Smooth and cardiac muscle
ACH (b)
Parasympathetic neuron
ACH
ACH
Adrenergic receptors
Sympathetic neuron NE
Ganglion Nicotinic-n receptors
Nicotinic-m receptors
(c)
Skeletal muscle
Somatic neuron ACH
(a) Illustrates a parasympathetic neuron with pre- and postganglionic nerve fibers innervating smooth or cardiac muscle via the muscarinic receptor. (b) Illustrates the nicotinic-n receptor located on the ganglia of both parasympathetic and sympathetic neurons. (c) Illustrates a somatic neuron that innervates skeletal muscle via nicotinic-m receptors. Chapter 7 • Drugs Affecting the Parasympathetic Nervous System
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or muscarine at these receptors are referred to as either cholinergic or muscarinic. Drugs that block ACH at the muscarinic receptors are referred to as anticholinergic or antimuscarinic. Presently, the terms cholinergic and anticholinergic are preferred.
receptor sites. The direct-acting drugs only increase activity at the cholinergic (muscarinic) sites. Figure 7.3 compares the receptor sites of action of the direct-acting and indirect-acting cholinergic drugs.
Nicotinic-Neural (Nn) Receptors
Direct-acting cholinergic drugs bind to the cholinergic (muscarinic) receptors. Acetylcholine is not useful as a drug because of its extremely short duration of action. Therefore, several derivatives of ACH were synthesized (bethanechol and carbachol) that produce effects like those of ACH, but they are more slowly inactivated by acetylcholinesterase. Consequently, the durations of action of these drugs are considerably longer than is the duration of action for ACH. In all other respects, the derivatives of ACH stimulate cholinergic receptors similarly to ACH.
The cholinergic receptors at the ganglionic sites of both sympathetic and parasympathetic nerves (as seen in Figure 7.2(b)) are known as nicotinic-neural (Nn) receptors. Acetylcholine is the neurotransmitter for these receptors. The term nicotinic is derived from the drug nicotine, which is an alkaloid obtained from the tobacco plant. Early pharmacologists also used nicotine to study the pharmacology of the ANS, since nicotine stimulates the autonomic ganglia (sympathetic and parasympathetic) in low doses and blocks the autonomic ganglia in high doses. Drugs that act like ACH or low doses of nicotine at these receptors are known as ganglionic stimulants. Drugs that block ACH at these receptors or act like high doses of nicotine are referred to as ganglionic blockers. The ganglionic drugs will be discussed in Chapter 8.
Nicotinic-Muscle (Nm) Receptors The cholinergic receptors at the neuromuscular junction (NMJ) of skeletal muscle (seen in Figure 7.2(c)) are known as nicotinic-muscle (Nm) receptors. Nicotine also stimulates or acts like ACH at the skeletal neuromuscular junction. Drugs that block the effects of ACH at the NMJ are referred to as neuromuscular blockers or skeletal muscle relaxants. The nerves and receptors associated with skeletal muscle are not part of the autonomic nervous system. Skeletal muscle is under voluntary control and belongs with the somatic division of the nervous system. The skeletal muscle relaxant drugs will be discussed in Chapter 9. LO 7.3
CHOLINERGIC DRUGS Cholinergic drugs mimic the actions of ACH at the cholinergic (muscarinic) receptors. Another term with essentially the same meaning is parasympathomimetic. Cholinergic drugs are subdivided into two groups: the direct-acting and the indirect-acting drugs ( Table 7:1). The direct-acting drugs bind to the cholinergic (muscarinic) receptors and produce effects similar to those of ACH. The indirect-acting drugs inhibit the enzyme acetylcholinesterase. The indirect-acting drugs that inhibit acetylcholinesterase increase the concentration and actions of ACH at all muscarinic and nicotinic 94
Direct-Acting Cholinergic Drugs
Pharmacological Effects The direct-acting cholinergic drugs primarily increase GI secretions and motility, increase urinary tract function (urination), and cause pupillary constriction (miosis). The effects of these drugs on the heart (decrease heart rate) and respiratory smooth muscle (bronchoconstriction) are usually clinically insignificant (review Table 5:1). In addition to the derivatives of ACH, there are a few alkaloids, such as muscarine and pilocarpine, that have parasympathomimetic effects. Muscarine has no clinical importance except in cases of accidental mushroom poisoning. Pilocarpine is another alkaloid that acts like ACH and is used only in the form of eyedrops for the treatment of glaucoma.
Clinical Indications Because of the short duration of ACH and some of its derivatives, the direct-acting cholinergic drugs are rarely used systemically. Bethanechol is the exception; this drug is administered orally to stimulate the urinary and intestinal tracts. Certain drugs (general anesthetics) and conditions, especially in the elderly, cause urinary retention and intestinal stasis (ileus). Bethanechol may be administered several times a day to stimulate urination and GI activity. The main adverse effects are due to overstimulation of the bladder and intestines, resulting in increased urinary frequency and diarrhea. Cholinergic drugs are used locally during ophthalmic examinations as miotics to constrict the pupils and in the treatment of glaucoma. In glaucoma there is increased intraocular pressure. Increased intraocular pressure will gradually destroy the retina of the eye and cause blindness. Topical application (eyedrops) of
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Table 7:1
Cholinergic Drugs and Their Major Clinical Indications Drug (Trade Name)
Clinical indications
Direct-acting drugs Acetylcholine (Miochol-E )
Miotic in ophthalmology
Bethanechol (Urecholine)
Urinary retention, postoperative ileus
Carbachol (Isopto carbachol)
Treatment of glaucoma
Pilocarpine (Isopto carpine)
Treatment of glaucoma
Indirect-acting drugs (anticholinesterases) Ambenonium (Mytelase)
Treatment of myasthenia gravis
Demecarium (Humorsol)
Treatment of glaucoma
Echothiophate (Phospholine)
Treatment of glaucoma
Edrophonium (Tensilon)
Diagnosis of myasthenia gravis
Neostigmine (Prostigmin)
Treatment of myasthenia gravis, postoperative ileus, and urinary retention; antidote to excessive cholinergic blockade with anticholinergic and skeletal muscle blockers Treatment of glaucoma, antidote to excessive cholinergic blockade with anticholinergics and skeletal muscle blockers
Physostigmine (generic)
Pyridostigmine (Mestinon)
Treatment of myasthenia gravis
Donepezil (Aricept)
Treatment of Alzheimer’s disease
Galantamine (Reminyl)
Treatment of Alzheimer’s disease
Rivastigmine (Exelon)
Treatment of Alzheimer’s disease
Tacrine (Cognex)
Treatment of Alzheimer’s disease
cholinergic drugs produces miosis (pupillary constriction), which promotes better drainage of intraocular fluid from the eye. This lowers pressure and helps prevent retinal damage.
cholinergic receptor sites. The anticholinesterase drugs are subdivided into the reversible inhibitors and the irreversible inhibitors of acetylcholinesterase.
Indirect-Acting Cholinergic Drugs
The reversible inhibitors are used in the diagnosis and treatment of myasthenia gravis and Alzheimer’s disease, and as antidotes to reverse the effects of drugs that block cholinergic and nicotinic receptors. Myasthenia
The indirect-acting drugs are known as the anticholinesterases. These drugs inhibit the enzyme acetylcholinesterase and allow the accumulation of ACH at all
Reversible Inhibitors
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neostigmine (2 to 4 hours), pyridostigmine (3 to 6 hours), and ambenonium (4 to 8 hours) are longer. These drugs are administered orally for the treatment of myasthenia gravis and intravenously to reverse the effects of excessive cholinergic blockade. The previously mentioned drugs are all quarternary amines (charged compounds) that do not cross the blood-brain barrier and produce effects only at peripheral receptor sites. Physostigmine is not a charged compound and does produce effects in the brain. It is used parenterally to reverse the central nervous system (CNS) effects of excessive anticholinergic blockade and as eyedrops in the treatment of glaucoma. Additional anticholinesterase drugs that primarily increase the actions of ACH in the brain are used in the treatment of Alzheimer’s disease (see below).
Figure 7.3 The Receptor Sites of Action for Cholinergic Drugs Direct-Acting Drugs (e.g., bethan bethanechol)
ACH Acetyl-CoA etyl tyl-C tyl-Co --Co CoA C Choline C Cho h lin liline e
ACH
Choline Choline Acetate
ACH is inactivated enzymatically by acetylcholinesterase
(a) Direct-Acting Drugs
Irreversible Inhibitors
ACH Acetyl-CoA etyl tyl-Co y -CoA -Co CoA Cholin Cho Choline h lin liline i e
ACH
Choline Choline Acetate
Indirect-acting drugs inhibit acetylcholinesterase, allowing buildup of ACH at all sites
(b) Indirect-Acting Drugs Cholinergic (muscarinic) receptor
Nicotinic-neural (Nn) receptor
Nicotinic-muscle (Nm) receptor
The neurotransmitter ACH normally stimulates all cholinergic receptor sites: cholinergic (muscarinic), nicotinic-neural (Nn), and nicotinic-muscle (Nm). (a) Direct-acting cholinergic drugs, like bethanechol (B), only stimulate the cholinergic (muscarinic) receptors. (b) Indirect-acting cholinergic drugs inhibit acetylcholinesterase and the metabolism of ACH. This allows the concentration of ACH to significantly increase in the synaptic cleft of all cholinergic nerve endings. Consequently, the indirect-acting drugs increase cholinergic activity at all receptor sites.
gravis is an autoimmune disease that causes skeletal muscle weakness and paralysis. By inhibiting acetylcholinesterase, the anticholinesterase drugs increase the concentrations of ACH at the Nm receptors, which increases the strength of muscular contraction. Edrophonium has the shortest duration of action, about 30 minutes. Myasthenia gravis is diagnosed by intravenous injection of a low dose of edrophonium. An increase in muscle strength that occurs within a minute or so is usually positive for myasthenia gravis. The durations of
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The irreversible inhibitors of acetylcholinesterase are derivatives of organophosphate compounds widely used as insecticides, pesticides, and chemical warfare agents. These compounds have extremely long durations of action because they form irreversible bonds with the acetylcholinesterase enzyme. Echothiophate (Phospholine) is the only drug used clinically; it is administered as eyedrops in the treatment of glaucoma. In larger doses these drugs produce severe toxicity, referred to as cholinergic crisis, that can quickly cause respiratory paralysis and death. All of the anticholinesterase drugs, reversible and irreversible, produce effects that are similar to those of ACH and parasympathetic stimulation (parasympathomimetic).
Adverse and Toxic Effects of Cholinergic Drugs
The most common adverse effects of these drugs are caused by excessive stimulation of the parasympathetic nervous system. The symptoms include nausea, vomiting, diarrhea, blurred vision, excessive sweating, muscular tremors, bronchoconstriction, bradycardia, and hypotension. In toxic overdosage, muscular paralysis and respiratory depression may cause death. The main antidote is the administration of anticholinergic drugs such as atropine that compete with ACH for the cholinergic (muscarinic) receptor and reverse the effects of excessive cholinergic stimulation.
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Figure 7.4 Auto-injectors Containing Antidotes A tropine and Pralidoxime
LO 7.4
CLINICAL INDICATIONS FOR ANTICHOLINESTERASE DRUGS The reversible anticholinesterase drugs are more widely used than the direct-acting cholinergic drugs. They are used in the treatment of glaucoma, myasthenia gravis, urinary retention, intestinal paralysis, Alzheimer’s disease and as antidotes to the curare-type skeletal muscle blockers and the anticholinergic drugs.
Topical Use in Glaucoma
Atropine and pralidoxime can be self-injected following excessive exposure to irreversible a nticholinesterase drugs (organophosphates) found in insecticides, pesticides, and chemical warfare agents.
Cholinergic Crisis Cholinergic crisis is the term usually used to describe the effects of excessive drug dosage in patients with myasthenia gravis, farmers overexposed to insecticides or pesticides, or individuals exposed to chemical warfare agents. At high concentrations ACH causes excessive stimulation of cholinergic (muscarinic) receptors, but blockade (paralysis) of nicotinic receptors. This may result in respiratory paralysis because respiratory muscles are skeletal (voluntary) in nature. In these situations, anticholinesterase drug administration must be stopped until the levels of ACH return to normal. Atropine can be administered to block the effects of excessive cholinergic (muscarinic) stimulation. Farmers who spray their fields with derivatives of the irreversible anticholinesterases (organophosphates) also may experience a cholinergic crisis. Unless protective masks or enclosed tractor cabs are used, the farmer may inhale too much of the insecticide or pesticide and develop signs of cholinergic crisis. With the irreversible drugs, the antidote is atropine to reverse the effects of excessive ACH and also an additional drug, pralidoxime (Protopam, Figure 7.4). Pralidoxime is a drug that can reactivate the acetylcholinesterase enzyme after it has been inhibited by an irreversible inhibitor. Pralidoxime is most effective immediately after organophosphate exposure. A process know as “aging,” where the enzyme becomes resistant to reactivation, can occur within minutes. Pralidoxime is also the antidote to organophosphate chemical warfare agents.
Several of these drugs are used topically as eyedrops to lower intraocular pressure in glaucoma. By inhibiting the metabolism of ACH, they increase ACH levels in the eye to produce miosis, improved drainage of intraocular fluid, and lower intraocular pressure.
Treatment of Myasthenia Gravis Myasthenia gravis is a disease of the skeletal muscle endplate where ACH functions to stimulate muscle tone and contraction. The condition is believed to be due to an autoimmune reaction where the body produces antibodies that attack the Nm receptor. The result is loss of skeletal muscle tone and strength. The eyelids droop and, as the disease progresses, there is difficulty in physical movement. Eventually patients may become bedridden and have difficulty breathing. The longeracting reversible anticholinesterase drugs, pyridostigmine and ambenonium, are preferred and used orally to increase ACH levels and increase skeletal muscle tone and strength.
Patient Administration and Monitoring Check and observe for signs of cholinergic overdosage, especially after parenteral administration: visual disturbances, salivation, nausea, increased frequency of urination, diarrhea, slow heart rate, respiratory difficulties, seizures (physostigmine). Explain to patient the common drug side effects: visual disturbances (especially after eyedrops), sweating, increased frequency of urination, and defecation. Instruct patient to report eye irritation or inflammation, excessive salivation, sweating, urination, diarrhea, slow pulse rate, muscle weakness, and respiratory difficulties.
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Treatment of Urinary Retention and Intestinal Stasis Urinary retention (also referred to as atony of the bladder) and intestinal stasis or paralysis (also referred to as paralytic ileus) are usually treated with neostigmine. The increased levels of ACH stimulate bladder contraction and intestinal peristalsis.
Treatment of Alzheimer’s Disease Alzheimer’s disease is a degenerative brain condition that occurs in some individuals with aging. There appears to be a loss of neuronal synapses and, in particular, a reduction of ACH levels in the brain. These changes cause memory loss, dementia, and general deterioration of mental function. Currently there are four reversible anticholinesterase inhibitors available that have demonstrated modest effects to delay the progression of mental deterioration. Tacrine (Cognex) was the first drug introduced; it is associated with more side effects than the others, particularly hepatic toxicity. Donepezil (Aricept) is approved for treatment of all stages of Alzheimer’s disease. Galantamine (Reminyl) and rivastigmine (Exelon) are the newest drugs approved for treatment of mild to moderate disease. These drugs are all centrally acting, reversible anticholinesterase inhibitors that increase ACH levels in the brain. Beneficial effects of the drugs are most notable in the early stages of the disease and lessen as the disease progresses. The most common side effects are nausea, vomiting, diarrhea, and other effects related to excessive cholinergic activity. A newer drug, memantine (Namenda) blocks excitatory glutamate receptors in the brain and appears to offer some protection against excessive excitation and nerve damage. Memantine is claimed to be better tolerated than the anticholinesterase inhibitors. Common side effects include headache, dizziness, confusion, coughing, and minor respiratory difficulties.
the cholinergic receptors (muscarinic) and produce effects similar to decreasing the activity of the parasympathetic system (parasympatholytic). This includes urinary and intestinal inhibition, cardiac stimulation (tachycardia), and central effects in the brain that can cause a variety of stimulant (seizures) and depressant (coma) effects. The antidote is usually to administer physostigmine because this drug can pass the bloodbrain barrier. The increased levels of ACH produced by physostigmine compete with the anticholinergic drug for the receptor. As the levels of ACH increase, the central effects of excessive anticholinergic blockade are reversed.
Clinical Use of Botulinum Toxin Botulinum toxin is derived from the toxin produced by the bacterium Clostridium botulinum. The toxin inhibits the release of ACH from cholinergic nerve endings. In skeletal muscle this action results in muscle paralysis. Local intradermal injections of the toxin (Botox Cosmetic) are used to temporarily decrease the wrinkling around the eyes, forehead, and face that occurs with aging ( Figure 7.5). Other preparations of the toxin (Botulinum toxin type A, Botox, and Botulinum toxin type B, Myobloc) are injected intramuscularly in muscle disorders such as strabismus, blepharospasm, cerebral palsy, and other spastic conditions to provide muscle relaxation. Injections usually last 1–3 months.
Figure 7.5 Woman Receiving Botox Injection to Lessen Skin Wrinkling for Cosmetic Purposes
Antidotes to Skeletal Muscle Blockers Skeletal muscle blockers (see Chapter 9) are used in surgery to produce paralysis of skeletal muscles (Nm receptor). At high doses they may cause respiratory paralysis. In these situations, administration of neostigmine will increase ACH levels and antagonize the actions of the skeletal muscle blockers.
Antidotes to Anticholinergic Drug Poisoning Anticholinergic drugs, such as atropine and scopolamine (see Anticholinergic Drugs section that follows) block
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LO 7.5
ANTICHOLINERGIC DRUGS The cholinergic blocking drugs that bind to the muscarinic receptors are referred to as the anticholinergic, or parasympatholytic, drugs. They act by competitive antagonism of ACH. In the presence of anticholinergic drugs, sufficient amounts of ACH are unable to bind to the cholinergic receptors to produce an effect. The oldest anticholinergic drugs, such as atropine and scopolamine, were obtained from the belladonna plant (deadly nightshade) and are commonly referred to as the belladonna alkaloids. Atropine, scopolamine, and the newer synthetic drugs are listed in Table 7:2.
Pharmacological Actions and Clinical Indications Cardiovascular System By blocking the effects of ACH, anticholinergic drugs decrease the activity of the vagus nerve (parasympathetic nerve) on the heart. Consequently, there is an increase in heart rate. In patients with excessively slow heart rates (bradycardia), atropine may be used to increase heart rate and atrioventricular conduction. Isoproterenol (beta drug) that stimulates beta-1 receptors also can be used to increase heart rate. However, for the chronic treatment of bradycardia, nonpharmacologic therapy with a cardiac pacemaker is usually preferred.
Respiratory System ACH increases the secretions of the respiratory tract and may cause bronchoconstriction. Anticholinergic drugs are administered preoperatively to inhibit secretions that can interfere with the administration of general anesthetics. In addition, ipratropium and tiotropium are anticholinergic drugs administered as aerosols that produce bronchodilation and are used in the treatment of asthma and chronic obstructive pulmonary disease (COPD) (see Chapter 32).
GI System Anticholinergic drugs reduce salivary and GI secretions. In addition, they decrease the motility of the GI tract and therefore they should not be administered when there is intestinal obstruction. The anticholinergic drugs are used as antispasmodics in GI disorders such as irritable bowel syndrome. In the treatment of peptic ulcers, the anticholinergic drugs, which decrease gastric acid secretion, have been replaced by newer and more effective drugs (see Chapter 33).
Genitourinary System Anticholinergic drugs inhibit urinary peristalsis and the voiding of urine. These drugs may be used in individuals
suffering from enuresis (urinary incontinence) to promote urinary retention and in the treatment of overactive bladder that involves spasm and increased urinary urgency. However, anticholinergic drugs are contraindicated in males with hypertrophy of the prostate gland. These drugs increase urinary retention and further increase the difficulty of urination associated with this condition.
Central Nervous System Most anticholinergic drugs that gain access to the brain produce a depressant effect, which generally results in drowsiness and sedation. Some over-the-counter preparations contain limited amounts of scopolamine and are used as sleep aids. At higher doses, there can be a mixture of both CNS stimulant and depressant effects. At toxic doses, both atropine and scopolamine may produce excitation, delirium, hallucinations, and a profound CNS depression that can lead to respiratory arrest and death. Anticholinergic actions are useful in the treatment of Parkinson’s disease (see Chapter 17) and as antiemetics (see Chapter 33) in the treatment of motion sickness.
Ocular Effects The anticholinergic drugs produce mydriasis (pupillary dilation) and cycloplegia (loss of accommodation). They are used in ophthalmology to facilitate examination of the retina and lens. Anticholinergic drugs increase intraocular pressure and should never be administered to patients with glaucoma. In glaucoma, there is a blockage of the drainage pathway for intraocular fluid. The anticholinergic effect causes pupillary dilation, which in glaucoma increases closure of the drainage pathway. The result can be a sudden increase in intraocular pressure and damage to the eye.
Adverse and Toxic Effects The most frequently occurring adverse effects of the anticholinergic drugs are caused by excessive blockade of the parasympathetic nervous system. The symptoms include dry mouth, visual disturbances, urinary retention, constipation, flushing (redness) and dryness of the skin, fever (hyperpyrexia), tachycardia, and symptoms of both CNS stimulation and depression. The effects on the skin are due to anticholinergic effects that inhibit the sweating mechanism and that vasodilate certain blood vessels to cause a flushing reaction. In toxic doses, hyperpyrexia and CNS depression can be severe and may be accompanied by depression of the vital centers in the brain. If untreated this may result in respiratory paralysis and death. The belladonna alkaloids are present in some overthe-counter preparations and in many common plant
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Table 7:2
Representative Anticholinergic Drugs and Their Main Clinical Uses Drug (Trade Name)
Preparations
Main clinical uses
Atropine (generic)
Tablets, parenteral injection
Antidote for cholinesterase inhibitor poisoning, anticholinergic effects
Atropine (Isopto atropine)
Ophthalmic drops, ointment
Ophthalmic examinations
Darifenacin (Enablex)
Tablets
Relief of urinary spasms, urgency, incontinence
Dicyclomine (Bentyl)
Tablets, syrup, parenteral injection
Intestinal disorders, diarrhea, irritable bowel syndrome
Flavoxate (Urispas)
Tablets
Relief of urinary spasms, urgency, incontinence
Glycopyrrolate (Robinul )
Tablets
Intestinal disorders, diarrhea
Hyoscyamine (Anaspaz)
Oral tablets, capsules, parenteral injection
Intestinal disorders, diarrhea, irritable bowel syndrome
Ipratropium (Atrovent)
Aerosol, metered-dose inhaler
Bronchodilation, asthma, COPD
Methscopolamine (Pamine)
Tablets
Intestinal disorders, spasms
Oxybutynin (Ditropan, Detropan XL)
Tablets, syrup, transdermal patch
Relief of urinary spasms, urgency, incontinence
Propantheline (Pro-Banthine)
Tablets
Intestinal disorders, diarrhea, irritable bowel syndrome
Scopolamine (generic) (Transderm scop)
Tablets, parenteral injection Skin patch
Intestinal disorders Motion sickness
Solifenacin (Vesicare)
Tablets
Relief of urinary spasms, urgency, incontinence
Tiotropium (Spiriva)
Aerosol, metered-dose inhaler
Bronchodilation, asthma, COPD
Tolterodine (Detrol, Detrol LA)
Tablets, capsules
Relief of urinary spasms, urgency, incontinence
Trospium (Sanctura)
Tablets, capsules
Relief of urinary spasms, urgency, incontinence
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Patient Administration and Monitoring Observe patient for signs of excessive anticholinergic effects, especially after parenteral administration: tachycardia, flushing of skin (redness), decreased urination, CNS stimulation or depression, respiratory difficulties. Explain to patient the common anticholinergic side effects: dry mouth, blurred vision (pupillary dilation), sedation, or mental confusion. Instruct patient to report excessive blurred vision, fast pulse rate, difficulty with urination, constipation, mental confusion, or hallucinations.
substances and noneatable plant berries. Poisoning usually occurs in children who have mistakenly eaten the berries. Such children usually develop fever, tachycardia, dryness and flushing of the skin, and mydriasis. Emergency treatment is essential. If sufficient quantities have been ingested, respiratory paralysis, coma, and death may occur within a few hours. Treatment involves inducing emesis or performing gastric lavage to limit absorption. Activated charcoal and saline cathartics are administered to inactivate the drug and accelerate its elimination. Physostigmine, given intravenously, antagonizes the actions of the anticholinergic drugs and is useful when CNS symptoms such as delirium and coma are present.
Geriatric patients are particularly susceptible to anticholinergic effects and should be observed more closely, especially for mental confusion and disorientation. Anticholinergic drugs are contraindicated in patients with narrow-angle glaucoma, males with prostate hypertrophy, and patients with urinary or intestinal obstruction. The antidote to anticholinergic overdose is administration of anticholinesterase drugs, especially physostigmine when there are CNS symptoms.
Overactive Bladder/Urge Incontinence Anticholinergic drugs such as oxybutynin (Ditropan, Ditropan XL), tolterodine (Detrol, Detrol LA), darifenacin (Enablex), and solifenacin (Vesicare) are administered to relax the urinary bladder and reduce urinary urgency. The latter two drugs have longer half-lives and allow once-daily dosing.
Intestinal Stasis/Postoperative Ileus Cholinergic drugs such as bethanechol (Urecholine) or the anticholinesterases such as neostigmine (Prostigmine) are administered to increase intestinal tone and motility.
Irritable Bowel Syndrome LO 7.6
PREFERRED TREATMENT FOR SELECTED CONDITIONS Urinary Retention/Difficulty in Urination After prolonged urinary catheterization, surgery with general anesthetics, or other conditions, there is often difficulty in urination. Cholinergic drugs such as bethanechol (Urecholine) or cholinesterase inhibitors such as neostigmine (Prostigmine) are preferred to increase urinary tone and motility in these situations. In males with benign prostatic hyperplasia, the preferred drugs to increase urinary flow are alpha-blockers such as tamsulosin (Flomax) or alfuzosin (Uroxatral ); these drugs were discussed in Chapter 6.
Anticholinergic drugs such as dicyclomine (Bentyl ), glycopyrrolate (Robinul ), or hyoscyamine (Anaspaz) are administered to decrease intestinal secretions and motility.
Myasthenia Gravis The preferred drug to increase ACH levels at the skeletal neuromuscular junction is pyridostigmine (Mestinon). Alternatives include ambenonium (Mytelase) or neostigmine (Prostigmine).
Alzheimer’s Disease The preferred drugs are the cholinesterase inhibitors. Galantamine (Reminyl ) and rivastigmine (Exelon) are currently indicated for mild to moderate disease while donepezil (Aricept) is indicated for all stages of Alzheimer’s disease. Memantine (Namenda) is a newer drug that also may be considered.
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Chapter Review Understanding Terminology Match the drug effect or drug use in the left column with the appropriate drug in the right column. Each answer can be used more than once. (LO 7.3, 7.4, 7.5) ___ 1. Reactivates acetylcholinesterase.
a. bethanechol (Urecholine)
___ 2. Directly stimulates cholinergic (muscarinic) receptor.
b. ambenonium (Mytelase)
___ 3. Increases ACH levels in the CNS.
c. scopolamine (Transderm Scop)
___ 4. Used to reverse CNS anticholinergic toxicity.
d. echothiophate (Phospholine)
___ 5. Used to treat myasthenia gravis.
e. atropine
___ 6. Used to prevent motion sickness.
f. physostigmine
___ 7. Used before surgery to dry respiratory secretions.
g. pralidoxime (Protopam)
___ 8. Indicated for treatment of Alzheimer’s disease.
h. tacrine (Cognex)
___ 9. Irreversibly inhibits acetylcholinesterase. ___ 10. Used to treat nonobstructive urinary retention. 11. Differentiate between parasympatholytic and parasympathomimetic. (LO 7.3, 7.5) 12. Explain the terms cholinergic and anticholinergic. (LO 7.1)
Acquiring Knowledge Answer the following questions. 1. What is the function of the parasympathetic nervous system? (LO 7.3) 2. What is the function of acetylcholinesterase? Where is it found? (LO 7.1) 3. Where are the three different cholinergic receptors located? What class of drug is needed to block each receptor? (LO 7.2) 4. How do the direct-acting and the indirect-acting cholinergic drugs produce their parasympathetic effects? (LO 7.3) 5. List the potential adverse effects of the cholinergic drugs. (LO 7.3) 6. List the potential adverse effects of the anticholinergic drugs. (LO 7.5) 7. What is the preferred drug treatment for myasthenia gravis? (LO 7.6)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. As a nurse working for a team of doctors in a busy practice, you are sometimes given the task of screening patients for potential prescription drug problems. Patient X has just been diagnosed as having colitis, for which his doctor has prescribed dicyclomine. You note that in his first visit last year, Patient X mentioned he takes the drug timolol. You decide you’d better check the PDR® to see what timolol is used to treat before Patient X starts taking the dicyclomine. What should you report to the doctor? (LO 7.5) 2. Your next-door neighbor knows you are studying pharmacology so she sometimes comes to you when she has questions about health problems. A few minutes ago, she came to your door in a state of panic. She said her 3-year-old had just swallowed some scopolamine tablets, which your neighbor takes for her irritable bowel syndrome. What should you do? (LO 7.5)
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3. Your elderly patient who was prescribed an antispasmotic drug for GI hyperactivity is complaining of increased sensitivity to light and notices that she has difficulty urinating. What do you think is happening to this patient? What class of drugs do you think she was most likely prescribed? What drug class would be indicated if her condition worsened and treatment was required? (LO 7.5) 4. Mr. Jones is being treated for myasthenia gravis. During his regular checkup you notice that he is sweating and his heart rate is below normal. You ask him how he’s feeling and he says he’s had diarrhea for the past few days and that he feels very weak. Can you explain what may be happening to Mr. Jones? Explain why some of his symptoms appear to be due to excessive cholinergic stimulation, yet he has skeletal muscle weakness. (LO 7.3, 7.4) 5. An elderly woman in a nursing facility is being treated with bethanechol for urinary retention. She is complaining of abdominal discomfort, excessive salivation, and feeling hot and sweaty. Could these symptoms be due to the medication? If so, what do they indicate? (LO 7.3) 6. A 28-year-old male has been diagnosed with irritable bowel syndrome. His health care provider has prescribed dicyclomine 20 mg TID. What side effects should be included in the patient c ounseling? (LO 7.5)
Multiple Choice Use your critical-thinking skills to answer the following questions. 1. Parasympathetic receptors located on the membranes of the internal organs are classified as (LO 7.2) A. alpha-1 B. nicotinic-neural (Nn) C. nicotinic-muscle (Nm) D. muscarinic 2. Select the pharmacologic effect produced by cholinergic drugs. (LO 7.3) A. increased heart rate B. increased gastrointestinal motility C. decreased urination D. pupillary dilation 3. Physostigmine (Eserine) is classified as a(n) (LO 7.3) A. direct-acting cholinergic drug B. reversible anticholinesterase inhibitor C. irreversible anticholinesterase inhibitor D. anticholinergic drug 4. Symptoms of cholinergic drug overdosage include (LO 7.3) A. slow pulse rate B. increased urination C. diarrhea D. all of the above 5. Anticholinergic actions include all of the following except (LO 7.5) A. bronchodilation B. increased heart rate C. increased gastrointestinal activity D. decreased respiratory secretions
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Chapter Review Continued 6. The antidote for atropine poisoning is (LO 7.3) A. scopolamine B. bethanechol C. neostigmine D. physostigmine 7. Tolterodine (Detrol) is indicated for treatment of (LO 7.5) A. motion sickness B. relief of urinary incontinence C. ophthalmic examinations D. glaucoma
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Which of the following are used for the treatment of myasthenia gravis? (LO 7.4) A. Tensilon B. Mytelase C. Prostigmin D. Mestinon 2. Select the conditions produced by anticholinergic drugs. (LO 7.5) A. mydriasis B. glaucoma C. cyclopegia D. sedation 3. Which of the following are not cholinergic receptors? (LO 7.2) A. muscarinic B. nicotinic-neural C. nicotinic-muscle D. sympathomimetic 4. Pick the correct pharmacological effects of direct-acting cholinergic drugs. (LO 7.3) A. respiratory paralysis B. urinary retention C. increased heart rate D. bronchodilation 5. Which of the following would be a preferred treatment for overactive bladder? (LO 7.6) A. Cognex B. Detrol C. Pilocar D. Bentyl
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Sequencing Place the processes in order from first to last as they happen in the body. (LO 7.1)
______________
______________
______________
First
______________ Last
Acetylcholinesterase deactivates ACH ACH released from storage vesicles Presynaptic nerve is stimulated ACH is stored in cholinergic nerve endings
Classification Place the correct drug under the condition it is most commonly used to treat. (LO 7.6) darifenacin
Exelon
galantamine
Detrol LA
carbachol
Mytelase
neostigmine
solifenacin
pyridostigmine
Cognex
Humorsol
pilocarpine
Glaucoma
Alzheimer’s disease
Urinary spasms
Myasthenia gravis
Documentation Based on the symptoms listed upon admission to the hospital, answer the following questions. (LO 7.5) Symptoms: flushed skin tachycardia difficulty breathing blurred vision a. What type of drug overdose is the patient likely suffering from? b. What is happening at the muscarinic receptors in this patient? c. What medications would be given to treat this overdose?
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Chapter Review Continued Labeling Fill in the missing labels. (LO 7.2)
ACH (a)
Parasympathetic neuron
ACH
ACH ACH
Parasympathetic neuron
(b)
ACH Sympathetic neuron NE
Ganglion Nicotinic-n receptors
(c)
Somatic neuron ACH
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Chapter 8
Drugs Affecting the Autonomic Ganglia DRUG CLASS AT A GLANCE OTC
NICOTINE GUM, LOZENGES, PATCHES
PRESCRIPTION NICOTINE INHALER, SPRAY, BUPROPION, VARENICLINE
SCHEDULED DRUGS
NO
FDA P REGNANCY CATEGORY
B, C, D
KEY TERMS ganglionic blocker: drug that blocks the nicotinic-neural (Nn) receptors and reduces the activity of the autonomic nervous system. ganglionic stimulant: drug that stimulates the nicotinic-neural (Nn) receptors to increase autonomic nervous system activity. nicotine: alkaloid drug in tobacco that stimulates ganglionic receptors. nicotinic-neural (Nn) receptor: cholinergic receptor at the autonomic ganglia.
INDICATIONS Smoking substitute, hypertension
Learning Outcomes
After studying this chapter, you should be able to
8.3 describe the main pharmacologic effects and uses of ganglionic blockers.
8.1 describe the pharmacological effects of ganglionic stimulation.
8.4 discuss the adverse effects associated with the use of ganglionic blocking drugs.
8.2 list the different drug preparations used in nicotine replacement therapy and the adverse effects associated with them.
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Introduction
The autonomic ganglia of both sympathetic and parasympathetic nerves are pharmacologically identical. Acetylcholine (ACH) is the neurotransmitter at both autonomic ganglia. Before the discovery of ACH, nicotine was found to stimulate the autonomic ganglia, and so the receptors at the ganglia were known as the nicotinic receptors. Currently they are more specifically classified as the nicotinic-neural (Nn) receptors. Drugs that stimulate the Nn receptors are called ganglionic stimulants, while drugs that block these receptors are called ganglionic blockers. There are very few clinical conditions where ganglionic stimulation or blockade is of significant clinical value. Nicotine-containing products that help smokers quit the tobacco habit and medications used in the treatment of severe hypertension are essentially the only drugs used clinically that act on autonomic ganglia.
LO 8.1
GANGLIONIC STIMULANTS Acetylcholine is the neurotransmitter at the autonomic ganglia that normally stimulates the nicotinic-neural (Nn) receptors (Figure 8.1). Individuals who use tobacco absorb nicotine, which produces ganglionic stimulation that increases both sympathetic and parasympathetic activity. Theoretically, if both autonomic divisions are stimulated at the same time, the physiological effects should cancel out. However, sympathetic stimulation usually predominates in the cardiovascular system while parasympathetic stimulation predominates in the gastrointestinal tract. Consequently, after smoking, there is usually an increase in heart rate, blood pressure, and GI activity. More importantly, nicotine stimulates nicotinic receptors in the brain that provide the central nervous system effects of tobacco use. The actions in the brain are also the cause of the dependency and habitual use of tobacco products.
Figure 8.1
As a drug class, drugs that stimulate autonomic ganglia have little clinical use. However, for individuals who want to quit the tobacco habit, there are nicotinecontaining preparations that substitute for tobacco. A number of nicotine-containing preparations are used in nicotine-replacement therapy (NRT). The purpose of NRT is to provide nicotine while the use of tobacco and the habit of smoking are discontinued. Preparations include chewing gum, lozenges, transdermal patches, oral inhalers, and nasal sprays. The intention of these products is to lessen the symptoms and withdrawal reactions caused by quitting the tobacco habit. Over time the use of these products can be reduced and then eliminated. There are also drugs that act in the brain to reduce the cravings for tobacco products. These drugs do not contain nicotine but are used to affect behavior and the cravings for nicotine and cigarette smoking. Bupropion
Illustration of an Autonomic Ganglion
Autonomic efferent innervation ACH Preganglionic fiber
ACH or NE Postganglionic fiber
Autonomic ganglion
Visceral effectors (cardiac muscle, smooth muscle, glands)
Nn receptors
Acetylcholine (ACH) is the neurotransmitter at the ganglion that stimulates nicotinic-neural (Nn) receptors on the cell membrane of the postganglionic nerve fiber.
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LO 8.2
Table 8:1
Drugs Used in the Treatment of Smoking Cessation Drug preparation
Trade Name
Dosage
Nicotine gum
Nicorette
2 mg (limit 30 pieces/day) 4 mg (limit 20 pieces/day)
Nicotine lozenges
Commit
2 and 4 mg (limit 20/day)
Nicotine patch
Nicoderm CQ Nicotrol
7, 14, 21 mg (16–24 hours/day) 15 mg (16 hours/day)
Nicotine inhaler
Nicotrol Inhaler
Inhaled by mouthpiece and cartridges (10 mg/supplies 4 mg), dosage varies with individual
Nicotine nasal spray
Nicotrol NS
0.5 mg/spray/nostril 1–2 sprays/hour, dosage varies with individual
Bupropion Wellbutrin, Zyban Varenicline
is an antidepressant (Chapter 14) that affects mood and is claimed to reduce the CNS effects of nicotine withdrawal. Varenicline is a drug that is claimed to block nicotine receptors in the brain to prevent nicotine from exerting its full effects. Behavioral counseling is also an important component in the effort to quit smoking. Table 8:1 lists the different drug preparations available for quitting the tobacco habit.
Chantix
Antidepressant drug used to reduce nicotine cravings 25-, 50-, 75-, 150-mg tablets 150 mg, sustained release 0.5- and 1-mg tablets, blocks effect of nicotine on CNS receptors
Figure 8.2 Pregnant Woman Drinking and Smoking a Cigarette
Cautions and Contraindications Pregnancy Nicotine has been shown to be harmful to the fetus. Consequently, tobacco and the use of nicotine substitutes should be avoided during pregnancy (Figure 8.2). These drugs are classified as Pregnancy Category D by the FDA.
Adverse Effects Common adverse effects of nicotine gum and lozenges include taste disturbances, mouth and jaw soreness, and GI disturbances such as nausea and heartburn. Transdermal patches can cause soreness at the patch site, changes in taste, GI disturbances, and nervousness. Oral inhalers and nasal sprays may cause local mouth and throat irritation, minor breathing difficulties, and GI disturbances.
At toxic doses, ACH and nicotine desensitize both Nn and Nm (skeletal muscle) receptors and can act like ganglionic blockers and block both ganglionic and skeletal neuromuscular transmission. This blockade can result in respiratory paralysis and death. Bupropion is capable of causing a large number of adverse effects that include dry mouth, insomnia, and a Chapter 8 • Drugs Affecting the Autonomic Ganglia
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Note to the Health Care Professional Quitting the smoking habit is difficult for most individuals. Frequently, smokers will use nicotine replacement therapy (NRT) products but continue to smoke or chew tobacco. This can lead to nicotine toxicity. Warn smokers of the danger of using NRT products while continuing to indulge in tobacco use.
Patient Administration and Monitoring Mecamylamine is a potent ganglionic blocker that can cause orthostatic hypotension and significant depression of the cardiovascular system. Observe the patient for signs of low blood pressure, slow heart rate, and respiratory difficulties. Explain to the patient the symptoms of low blood pressure such as weakness, dizziness, and feelings of faintness, and to be careful when changing body position since this can cause orthostatic hypotension.
variety of GI disturbances. Also numerous neurological and neuropsychiatric effects such as confusion, hostility, and agitation are possible. The most common adverse effects of varenicline are nausea, vomiting, constipation, and headaches. In addition, psychiatric disturbances, mental depression, and suicidal ideation have been reported. In addition, after the first week of treatment, nicotine-containing products should not be taken during therapy with varenicline. LO 8.3
GANGLIONIC BLOCKERS Ganglionic blockers bind to and block Nn receptors. Since the sympathetic division has greater control over regulation of blood pressure, the ganglionic blockers cause a reduction in blood pressure and are primarily used in the treatment of severe hypertension. By blocking Nn receptors at the ganglia, the ganglionic blockers decrease the activity of the cardiovascular, gastrointestinal (GI), and genitourinary systems. The major effects are hypotension, bradycardia, decreased intestinal secretions and motility, and reduced urination. In males, impotence may occur. In addition, there are usually varying degrees of visual disturbances such as mydriasis and cycloplegia. The ganglionic blockers are potent drugs that are associated with numerous autonomic adverse effects. Clinical use of these drugs is limited and mainly indicated for treatment of severe hypertension.
Pharmacokinetics The first ganglionic blockers that were discovered (hexamethonium, pentolinium, and trimethaphan) possessed a quaternary ammonium ion. Quaternary ammonium ions are permanently charged molecules and are poorly absorbed from the GI tract. Trimethaphan (Arfonad ) is the only one currently available and it is administered by IV injection when blood pressure needs to be rapidly 110
Instruct the patient to notify the physician if symptoms of low blood pressure such as slow heart rate, constipation, or difficulties with urination occur.
reduced. Mecamylamine, another ganglionic blocker, is not a quaternary ion and is almost completely absorbed after oral administration.
Clinical Indications The only ganglionic blocker currently available for chronic use is mecamylamine (Inversine). The main indication for mecamylamine is for the treatment of severe hypertension when other drugs have not been effective. The pharmacologic action of mecamylamine is mainly due to ganglionic blockade of sympathetic ganglia, which causes profound vasodilation. Although mecamylamine is a very potent antihypertensive drug, it produces numerous adverse effects that many patients cannot tolerate. Mecamylamine usually is used in combination with other antihypertensive drugs, which allows reduction of the mecamylamine dosage and the frequency and severityy of adverse effects. LO 8.4
ADVERSE EFFECTS OF GANGLIONIC BLOCKERS Almost all of the adverse effects of the ganglionic blockers are caused by excessive blockade of the autonomic ganglia. The result is a combination of anticholinergic and antiadrenergic effects, which usually include decreased GI activity (dry mouth and constipation), visual disturbances (mydriasis and cycloplegia), decreased cardiovascular function (hypotension and decreased cardiac output), and decreased genitourinary function (urinary retention and impotency). The ganglionic blockers are contraindicated in patients with glaucoma because the mydriatic effect increases intraocular pressure.
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Table 8:2
Drug Interactions with Ganglionic Blocking Drugs Drug class
Result
Adrenergic drugs
Antagonism of antiadrenergic effect of ganglionic blockade, especially on cardiovascular system
Adrenergic blocking drugs
Additive antiadrenergic effect to produce hypotension and possible cardiovascular collapse
Cholinergic drugs
Antagonism of anticholinergic effect of ganglionic blockade, especially on GI and urinary tracts
Anticholinergic drugs
Additive anticholinergic effect
Vasodilator drugs
Additive vasodilating effect to produce hypotension and possible cardiovascular collapse
Drug Interactions Many drugs act on autonomic receptors, and the possibility of a drug interaction with ganglionic blockers is significant. Table 8:2 lists the potential drug interactions with ganglionic blockers.
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Chapter Review Understanding Terminology Answer the following questions. 1. Differentiate between a ganglionic stimulant and a ganglionic blocker. (LO 8.1, 8.3) 2. What is the name of the cholinergic receptors at the ganglia? (LO 8.1)
Acquiring Knowledge Answer the following questions. 1. What neurotransmitter regulates ganglionic transmission? (LO 8.1) 2. List the main effects of ganglionic stimulation. (LO 8.1) 3. List the main effects of ganglionic blockade. (LO 8.3) 4. What are the main therapeutic uses of the ganglionic blocking drugs? (LO 8.3) 5. List the adverse effects of the ganglionic stimulants used in nicotine replacement therapy. (LO 8.2) 6. List the adverse effects of the ganglionic blocking drugs. (LO 8.4) 7. What other drugs might interact with the ganglionic blockers? (LO 8.4)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. Assume that you work in a health maintenance organization (HMO), where you act as patient liaison. Patients are encouraged to talk over problems with you if they feel that the problems have not been resolved by a doctor or if they feel uncomfortable discussing the problems with a doctor. One of the patients wants to talk to you about an “embarrassing problem.” He says that ever since he started taking that “strong medicine” for his high blood pressure, he hasn’t been able to make love to his wife. He also has a dry mouth, and he’s constipated all of the time. What drug is the patient most likely taking? (LO 8.3, 8.4) 2. A patient has been brought by ambulance to the emergency room where you work. He’s suffering from hypotension, and he’s on the verge of cardiovascular collapse. The patient’s wife, who accompanied him in the ambulance, says he was fine until he took some new medication for his high blood pressure. She has the bottle with her—the medication is mecamylamine. You ask her if he’s taking any other medicine, and she replies that he takes propranolol for his angina. What is producing these effects in this patient? (LO 8.3, 8.4) 3. A young man brought into the emergency room could hardly walk, had difficulty breathing, and had very low blood pressure. Upon questioning he said he had been chewing some type of gum to help him quit smoking. He admitted that he was still smoking a pack a day. What is going on with this patient? (LO 8.2)
Multiple Choice Use your critical-thinking skills to answer the following questions. 1. The receptors located on the ganglia of both autonomic nerve divisions are (LO 8.1) A. nicotinic-neural (Nn) B. nicotinic-muscle (Nm) C. muscarinic D. anticholinergic
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2. The effects produced by ganglionic stimulation include (LO 8.1) A. increased heart rate B. increased intestinal activity C. increased blood pressure D. all of the above 3. Pharmacologic effects produced by mecamylamine (Inversine) include (LO 8.3) A. increased urination B. decreased blood pressure C. diarrhea D. all of the above 4. At high or toxic doses, nicotine may cause (LO 8.2) A. ganglionic stimulation B. ganglionic blockade C. skeletal muscle contraction D. increased respiration function 5. The drug that blocks nicotinic receptors in the brain is (LO 8.2) A. trimethaphan B. atropine C. varenicline D. mecamylamine
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Which of the following is an effect of ganglionic blockade? (LO 8.3) A. hypotension B. reduced urination C. bradycardia D. impotence 2. Drugs used in smoking cessation come in what dosage forms? (LO 8.2) A. lozenges B. inhalers C. injectables D. patches 3. Ganglionic blocking drugs interact with which types of drugs? (LO 8.4) A. cholinergic B. anticholinergic C. adrenergic D. antiadrenergic 4. Ganglionic blocking drugs have which of the following adverse effects? (LO 8.4) A. hypertension B. dry mouth C. decreased ocular pressure D. diarrhea
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Chapter Review Continued 5. The adverse effects of varenicline are (LO 8.2) A. constipation B. suicidal thoughts C. headaches D. hostility
Classification Place the following in the proper drug classification. Inversine
trimethaphan
Commit
Wellbutrin
Nicorette
Pentolinium Smoking cessation
Ganglionic blockers
Matching Match the following effects with ganglionic stimulant or blocker. (LO 8.1) a. stimulant b. blocker 1. 2. 3. 4. 5. 6.
_____ _____ _____ _____ _____ _____
increased GI motility increased heart rate mydriasis reduced urination hypotension increased blood pressure
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Chapter 9
S keletal M uscle R elaxants DRUG CLASS AT A GLANCE OTC
NO
PRESCRIPTION
YES
SCHEDULED DRUGS
NO
FDA PREGNANCY CATEGORY
C, D
INDICATIONS Reduce muscle spasticity, adjuncts to anesthesia, assist intubation procedures
KEY TERMS black box warning (boxed warning): a warning that appears in the instructions for use surrounded by a thick black box to alert medical professionals to serious or life-threatening adverse effects associated with the drug usage. centrally acting skeletal muscle relaxant: drug that inhibits skeletal muscle contraction by blocking conduction within the spinal cord. depolarizing blocker: produces paralysis by first causing nerve transmission, followed by inhibition of nerve transmission. fasciculation: twitchings of muscle fiber groups. hyperthermia: abnormally high body temperature. incompatibility: undesirable interaction of drugs not suitable for combination or administration together. intrathecal: space around the brain and spinal cord that contains the cerebrospinal fluid. malignant hyperthermia: condition in susceptible individuals resulting in a life-threatening elevation in body temperature. microfilaments: minute fibers located throughout the cytoplasm of cells, composed of the protein actin, that maintain the structural integrity of a cell.
mitochondria: normal structures responsible for energy production in cells. myelin: the fatty substance that covers and protects nerves and allows efficient conduction of action potentials down the axon. neuromuscular junction (NMJ): space (synapse) between a motor nerve ending and a skeletal muscle membrane that contains acetylcholine (ACH) receptors. nicotinic-muscle (Nm) receptor: cholinergic receptor located at the neuromuscular junction of skeletal muscle. nondepolarizing blocker: produces paralysis by inhibiting nerve transmission.
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peripheral skeletal muscle relaxant: drug that inhibits muscle contraction at the neuromuscular junction or within the contractile process. potentiates: produces an action that is greater than either of the components can produce alone; synergy. sarcolemma: a thin membrane enclosing a striated (skeletal) muscle fiber. sarcoplasm: the cytoplasm of a striated (skeletal) muscle fiber sarcoplasmic reticulum: specialized organelle in the muscle cell that releases calcium ions during muscle contraction and absorbs calcium ions during relaxation. Schwann cell: any cell that covers the axons in the peripheral nervous system and forms the myelin sheath. spasmolytics: drugs that relieve, interrupt, or prevent muscle spasms (intermittent muscle contractions often associated with pain). synaptic knob: contains vesicles that store and release neurotransmitters. synaptic vesicles: a small membrane-bound structure in the axon terminals of nerve cells that contains neurotransmitters and releases them when an action potential reaches the terminal. vagolytic action: inhibition of the vagus nerve to the heart, causing the heart rate to increase (counteraction to vagal tone that causes bradycardia). vasodilator: substance that relaxes the muscles (sphincters) controlling blood vessels, leading to increased blood flow.
Learning Outcomes
After studying this chapter, you should be able to 9.1 describe at least two ways in which skeletal muscles may be relaxed. 9.2 explain why muscle relaxation is necessary during diagnostic and surgical procedures. 9.3 examine how these drugs may alter the ability to control respiration.
9.4 explain how tranquilizers relax skeletal muscles through a different mechanism of action than nondepolarizing blockers. 9.5 identify which drugs are used in the chronic treatment of spastic muscle disorders. 9.6 list three potential adverse effects associated with muscle relaxants.
Introduction
Contraction of skeletal muscles is voluntarily controlled by impulses that originate in the central nervous system (CNS). Impulses from the brain are conducted through the spinal cord to the somatic motor neurons (Figure 9.1). Somatic motor neurons eventually connect with skeletal muscle fibers forming a neuromuscular junction (NMJ). The neuronal endings of the somatic motor fibers contain the neurotransmitter acetylcholine (ACH). When ACH is released into the neuromuscular synapses, it combines with cholinergic receptors known as nicotinic-muscle (Nm) receptors. Although these receptors are cholinergic, they are not identical to the muscarinic (parasympathetic) and ganglionic receptors previously discussed in Chapter 5. Review the terminology for the different cholinergic receptor sites presented in Chapter 7. Depolarization of the muscle fibers occurs when ACH combines with the Nm receptors. Following depolarization, the contractile elements of the muscle fibers (actin and myosin) produce muscle contraction. Muscle relaxation occurs after ACH is hydrolyzed by acetylcholinesterase; this
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terminates the action of ACH. Skeletal muscle function is essential to life, since respiration depends upon the rhythmic contraction of the diaphragm and chest muscles. In addition, skeletal muscle tone permits coordinated movement of the entire body to maintain posture. This muscle activity occurs continually without our conscious awareness.
LO 9.1
LO 9.2
SKELETAL MUSCLE RELAXANTS
CLINICAL INDICATIONS
Many drugs inhibit skeletal muscle contraction by interfering with neuromuscular function. Drugs that inhibit skeletal muscle contraction by blocking conduction within the spinal cord are known as centrally acting skeletal muscle relaxants (Figure 9.2, site 1). In contrast, peripheral skeletal muscle relaxants inhibit muscle contraction at the NMJ (Figure 9.2, site 2) or within the contractile process (Figure 9.2, site 3). Motor neuron axons from the spinal cord enter the muscle fibers. The unmyelinated nerve fibers end in the NMJ (Figure 9.2, site 2). Presynaptic ends contain vesicles of acetylcholine. When triggered, acetylcholine is released into the synapse to bind with the nicotinicmuscle (Nm) receptors on the other side of the junction/ synapse. This receptor binding with acetylcholine enables sodium ions to move into the cells and potassium ions to move out of the muscle cells (depolarization). As depolarization spreads across the surface of the muscle fiber, calcium ions are released and muscle contraction occurs. Regardless of the site of action, drugs classified as skeletal muscle relaxants are clinically valuable because they selectively inhibit neuromuscular function. This inhibition then results in skeletal muscle relaxation.
Skeletal muscle relaxation is desirable in spastic diseases (multiple sclerosis and cerebral palsy), conditions in which the spinal cord has been damaged (trauma, paraplegia), and injuries in which pain accompanies overexertion of the muscles. In addition, surgical and orthopedic procedures and intubation (for example, bronchoscopy) are often facilitated by the use of skeletal muscle relaxants. Without administering these agents prior to invasive diagnostic procedures, there is a greater possibility for the reacting muscles to tear or become strained.
Figure 9.1
LO 9.3
LO 9.4
P ERIPHERALLY ACTING S KELETAL M USCLE R ELAXANTS Mechanism of Action Neuromuscular blockers inhibit skeletal muscle contraction by interfering with the nicotinic-muscle receptors. There are two types of neuromuscular blockers: nondepolarizing (curare and pancuronium) and depolarizing (succinylcholine).
Somatic Efferent Pathway
Somatic efferent innervation
ACH Myelinated fiber
Spinal cord
Somatic effectors (skeletal muscles)
The entire distance from the CNS to the skeletal muscle fiber (effector) is one neuron. Acetylcholine (ACH) is the only neurotransmitter.
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Figure 9.2
Sites of Action of Skeletal Muscle Relaxants
Direct-Acting Relaxant: Dantrolene
Somatic motor neuron Centrally Acting Relaxant: Baclofen Carisoprodol Diazepam Methocarbamol Orphenadrine Tizanidine
3 2 Motor nerve fiber 1
Myelin Schwann cell Basal lamina
Sarcolemma
Synaptic knob Synaptic vesicles (containing ACH)
2
Neuromuscular Relaxants: A. Depolarizing Succinylcholine B. Nondepolarizing Curare Cisatracurium Mivacurium Pancuronium Vecuronium
ACH receptors Synaptic cleft
Nucleus
Junctional folds
Myofilaments
Site 1 is impulse conduction from the CNS through the spinal cord, where the centrally acting muscle relaxants work. Site 2 is the neuromuscular junction (NMJ), where the depolarizing and nondepolarizing muscle relaxants work. The insert shows an individual NMJ. Site 3 is the skeletal muscle, where direct-acting drugs inhibit calcium ion release from the cell body. A complete list of skeletal muscle relaxants is presented in Tables 9:1 and 9:2.
The nondepolarizing blockers combine with the nicotinic-muscle receptors but do not stimulate the receptors. These agents occupy the nicotinic-muscle sites so that ACH cannot combine with the receptors and depolarization cannot occur (nondepolarizing, no depolarization). Curare, the original blow-dart poison you’ve seen in the movies, is the prototype of these drugs. Although curare use in the medical setting has been replaced by newer synthetic nondepolarizing blockers, the term curare-like effect is still used to identify side effects or symptoms associated with skeletal muscle paralysis and respiratory arrest. The nondepolarizing blocking drugs used today are easily recognized because their name ends in -curium or - curonium. Table 9:1 shows examples of available
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nondepolarizing blocking drugs such as atra curium, mivacurium, pancuronium, rocuronium, and vecuronium. The depolarizing blockers inhibit muscle contraction by a two-step process: (1) succinylcholine attaches to the nicotinic-muscle receptors and induces depolarization, observed as muscle fasciculations; and (2) then succinylcholine alters the nicotinic-muscle receptors so that they cannot respond to endogenous ACH stimulation. This phase is the neuromuscular blockade. Succinylcholine is the only available depolarizing neuromuscular blocking drug. If you can remember that acetylcholine is the neurotransmitter in the NMJ, then it should be easy to remember succinylcholine is the drug that stimulates (depolarizes) before it blocks the receptor. A small fact that might account for this action is that
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Table 9:1
Peripheral Skeletal Muscle Relaxant Doses and Routes of Administration Drug (Trade Name)
Type
Adult dose
Atracurium besylate*
Nondepolarizing
0.4–0.5 mg/kg IV bolus
Cisatracurium besylate (Nimbex)
Nondepolarizing
0.15 or 0.2 mg/kg IV
Dantrolene (Dantrium)**
Direct-acting
25 mg PO BID, QID
Mivacurium
Nondepolarizing
0.15 or 0.2 mg/kg IV
Pancuronium bromide***
Nondepolarizing
0.06–0.1 mg/kg IV
Rocuronium bromide (Zemuron)***
Nondepolarizing
0.6–1.2 mg/kg IV
Succinylcholine chloride (Anectine, Quelicin)***
Depolarizing
0.3–1.1 mg/kg IV, 1–2 mg/ml at 2.5 mg/min continuous IV infusion
Tubocurarine (curare; presented for historic reference)
Nondepolarizing
—
Vecuronium bromide (Norcuron)
Nondepolarizing
0.08–0.10 mg/kg IV
Indications * preparation for surgery, ** muscle spasticity, *** during surgery.
succinylcholine is actually two acetylcholine molecules back-to-back.
Route of Administration The nondepolarizing neuromuscular blockers are administered intravenously (IV). Examples of the IV doses of the peripheral neuromuscular blockers are presented in Table 9:1. The warning box that appears in the pancuronium FDA-approved instructions for use says, “This drug should be administered by adequately trained individuals familiar with its actions, characteristics, and hazards.” This certainly applies to all parenterally administered NMJ blocking drugs, both nondepolarizing and depolarizing. Following a single injection of a nondepolarizing blocker, neuromuscular blockade occurs within 3 to 5 minutes and lasts from 20 to 30 minutes. The muscles of the eyes and face are the first to become relaxed, followed by the limbs, trunk, and diaphragm. Recovery of muscle function occurs as the drug is metabolized and excreted. As a class, these drugs are not similar in where and how they are metabolized before being excreted. Mivacurium is metabolized by plasma cholinesterases, while rocuronium is metabolized in the liver and cisatracurium
is spontaneously degraded in the plasma. The duration of action, therefore, varies with the type of metabolism the drug undergoes. Curare, mentioned for historical reference, has a duration of action up to 60 minutes, while mivacurium is the shortest-acting nondepolarizing blocker, lasting 10 to 20 minutes. Pancuronium has a duration of action more than 30 minutes, but the remaining nondepolarizing blockers cited in Table 9:1 have an intermediate duration of action up to 30 minutes. The indication for use (i.e., tracheal intubation), duration of drug action, and condition of the patient will determine whether multiple administration or continuous IV infusion is required. The depolarizing blocker succinylcholine is metabolized so rapidly that it is often administered by intravenous infusion to maintain skeletal muscle relaxation. Succinylcholine is rapidly hydrolyzed by the enzyme plasma cholinesterase, specifically butyrylcholinesterase, which is present in the blood. Some individuals do not have enough of these general plasma cholinesterases, or because of a genetic abnormality, they produce an abnormal (atypical) enzyme. These people metabolize succinylcholine very slowly, so its duration of action and potential for toxicity to occur increase.
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As you can see in Table 9:1, there are many more nondepolarizing blockers (six) available for use today than depolarizing blockers (one). A goal of drug development in this class has been to find a drug that has a quick onset and duration of action with minimal adverse effects, primarily to replace succinylcholine. Well, succinylcholine is still with us and every new drug has some nontherapeutic effect(s) because of its site and mechanism of action. Nevertheless, the search for a new drug continues.
Effects on Cardiopulmonary Systems Although the primary site of action is the NMJ, neuromuscular blockers also produce cardiovascular changes at therapeutic doses through a different mechanism of action. Pancuronium has no effect on the autonomic ganglia or histamine release; however, it may cause tachycardia by blocking the vagal tone on the sino-atrial (SA) node of the heart (vagolytic action). Succinylcholine has been reported to produce ventricular arrhythmias and changes in blood pressure, which vary with the amount of drug administered. This depolizaring blocker does not have a direct effect on cardiac muscle (myocardium), but it does act at the ganglionic and muscarinic sites. Stimulation of these other cholinergic receptor sites can result in changes in heart rhythm, including cardiac arrest. Since the depolarization action of succinylcholine causes potassium leakage from the muscle cells, patients with electrolyte imbalances (burns or trauma) may develop arrhythmias more easily. Vecuronium has been reported to have little or no effect on the heart or blood pressure. Even when used in patients with pheochromocytoma (a tumor on the adrenal gland that secretes adrenaline), there were no remarkable changes in cardiovascular monitoring. Some of the blockers (atracurium, mivacurium, succinylcholine) cause a release of histamine from mast cells, which can lead to the production of bronchospasms and increased bronchial secretions in sensitive patients. Asthmatic patients are especially sensitive to the respiratory complications induced by histamine. Therefore, in asthmatic patients, the neuromuscular blocking drug will be selected that minimizes bronchial (respiratory) complications. Clinical signs and symptoms of histamine release also may include hypotension (most common) and tachycardia (see Chapter 31, Antihistaminic Drugs and Mast Cell Release Inhibitors). It is not unusual for an H1-antihistamine to be given as a premedication to block potential classic histamine effects of the neuromuscular blocking drugs.
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LO 9.6
ADVERSE AND TOXIC EFFECTS The major toxicity associated with all neuromuscular blockers is paralysis of the respiratory muscles. This is life-threatening because the patient can no longer control breathing, consciously or unconsciously. Skeletal muscle paralysis caused by the nondepolarizing blockers may be reversed by the use of neostigmine or edrophonium. Neostigmine and edrophonium inhibit acetylcholinesterase so that ACH accumulates within the junctions. The ACH displaces the blocker from the nicotinic-muscle receptors and, since their receptors are not damaged or changed, initiates depolarization and muscle contraction. An added benefit of neostigmine and edrophonium is their ability to directly stimulate the nicotinic-muscle receptors so that skeletal muscle paralysis is reversed. A new drug with a relatively unique mechanism of action, sugammadex, was submitted for U.S. FDA review recently. Sugammadex is the first in a new class of drugs, known as selective relaxant binding agents (SRBA). This drug reverses the neuromuscular blockade of nondepolarizing blockers by selectively encapsulating and chelating the blocker. It has a special affinity for rocuronium. Although it hasn’t yet been approved for use in the United States, it does speak to the continued interest in finding new drugs that affect the neuromuscular blockade. Succinylcholine overdose presents a special problem because this drug alters the ability of nicotinic-muscle receptors to become stimulated. There is no known antidote that reverses the neuromuscular blockade produced by succinylcholine. Administration of the anticholinesterase drugs may worsen the respiratory paralysis. Respiration must be supported artificially until the drug is metabolized and receptor responsiveness returns to normal. Skeletal muscle paralysis may be dangerously prolonged when succinylcholine is used in a patient who has atypical plasma cholinesterase. Succinylcholine produces an unusual acute toxicity that is probably due to an existing genetic abnormality in 1 out of 20,000 individuals. Occasionally, a normal dose of succinylcholine in combination with an inhalation anesthetic produces a condition known as malignant hyperthermia. This condition is associated with a drastic increase in body temperature, acidosis, electrolyte imbalance, and shock. The mechanism by which hyperthermia occurs is believed to be related to the anesthetic-induced potentiation of calcium hyperreactivity in susceptible individuals. The
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hyperactive biochemical reactions progress so quickly that treatment must be started immediately to reduce the risk of death. Treatment of hyperthermia includes reducing body temperature with ice packs and controlling arrhythmias and acidosis with appropriate drugs. Unfortunately, the incidence of fatality in malignant hyperthermia is high. Prevention is primarily directed at obtaining a good family history about other episodes of difficulty during operative procedures. Muscle biopsy and elevated muscle enzyme levels may identify potentially sensitive patients. Such a workup prior to an operation allows the surgical team to avoid the use of sensitizing agents. Succinylcholine has a black box warning in its FDA-approved instructions for use that states: “Succinylcholine has been associated with rapid muscle breakdown resulting in life-threatening heart rhythms, cardiac arrest, and death in children. Male children younger than 8 years of age seem to be at a higher risk, but cases have also been reported in adolescents. Because it is hard to determine which children may be at risk, Succinylcholine should only be used in an emergency situation.” This risk is identified for use in children. There still are situations where succinylcholine may be used to facilitate skeletal muscle relaxation (electroconvulsive therapy) or rapid tracheal intubation (emergency airway management). Its use is dependent on patient age, concomitant medical conditions in the patient, and training and experience of the anesthesiologist, surgical team, or emergency medical team.
Cautions and Drug Interactions Neuromuscular blocking drugs should be used with extreme caution in patients with impaired neuromuscular function (myasthenia gravis and spinal cord lesions). Any medication that inhibits skeletal muscle function potentiates the action of neuromuscular blockers. Antibiotics (neomycin, streptomycin), antiarrhythmic drugs, and some general anesthetics (halogenated gases like isoflurane, halothane) directly inhibit neuromuscular function, causing skeletal muscle relaxation. Succinylcholine-induced neuromuscular blockade is potentiated by drugs that promote a loss of potassium, such as diuretics and digitalis. In contrast, drugs that stimulate the nicotinic-muscle receptors or inhibit acetylcholinesterase antagonize nondepolarizing blockers. Drug interactions associated with skeletal muscle relaxants can potentiate or eliminate the pharmacologic action of muscle relaxants. Drugs that decrease the effect of any neuromuscular blocker include corticosteroids, carbamazepine, insecticides, acetylcholinesterase inhibitors, and theophylline. Drugs that increase
the effect of muscle relaxants include alcohol, antiarrhythmics (lidocaine, procainamide, quinidine), antibiotics (clindamycin, kanamycin, lincomycin, neomycin, pipericilllin, streptomycin, tetracyclines), general anesthetics, narcotic analgesics, tranquilizers, and sedatives. Succinylcholine is potentiated by digitalis and diuretics because these drugs induce a shift in potassium ions that enhances the action of succinylcholine. The only contraindication is the use in patients with a known hypersensitivity to any of these drugs. The nondepolarizing and depolarizing neuromuscular blockers are prepared as solutions for parenteral administration. Mixing some solutions can result in drug incompatibility and should be avoided. Drug incompatibility may result in discoloration of the solution, precipitation of drug, or, most important, alteration of drug potency. Succinylcholine has been reported to be unstable when mixed in alkaline solution (pH > 7.0). Admixture to solutions of barbiturates should be avoided because the combination results in hydrolyzation (breakdown) of succinylcholine.
Clinical Indications The peripheral neuromuscular blockers are used primarily before (premedication) and during surgical procedures (surgical relaxation) to relax abdominal or intrathoracic skeletal muscles. These agents are also used during electroconvulsive shock therapy and tetanus therapy to reduce muscle spasms. Airway management in emergency situations requires the use of these drugs to facilitate tracheal intubation. Airway management is the most important skill for an emergency physician to master because failure to secure an adequate airway can quickly lead to death or disability. Similarly, for diagnostic procedures such as laryngoscopy, the trachea must be relaxed to avoid muscle strain against the endoscope. Because of its short action, succinylcholine may be used to aid intubations for surgical procedures. Cisatracurium may be preferred in nonemergency situations because it has an intermediate duration of action and is not associated with histamine release. This permits control of the muscle relaxation without the hypotension or bronchospasm associated with histamine. Neuromuscular blockers are used in an ICU setting with critically ill patients who are compromised by their existing conditions of bronchospasm or chronic obstructive pulmonary disease (COPD), making it difficult for them to be properly externally ventilated. Peripheral neuromuscular blockers can reduce chest wall resistance (muscle relaxation), thereby increasing compliance and ventilation (oxygen/ carbon dioxide exchange).
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LO 9.1
LO 9.5
LO 9.6
D IRECT-ACTING S KELETAL M USCLE R ELAXANTS Dantrolene is considered a direct-acting peripheral skeletal muscle relaxant because it inhibits skeletal muscle fiber contraction by interfering with calcium ion release within the muscle fiber (Figure 9.2, site 3).
continued use. Any drug that decreases muscle strength or depresses the CNS may potentiate the muscle weakness produced by dantrolene. Drugs that increase the effect of dantrolene on skeletal muscle include alcohol, antiarrhythmics (lidocaine, procainamide, quinidine), antibiotics (clindamycin, kanamycin, lincomycin, neomycin, pipericilllin, streptomycin, tetracyclines), general anesthetics, narcotic analgesics, tranquilizers, and sedatives.
Mechanism of Action
LO 9 9.1 .1
LO 9 9.2 .2
Dantrolene prevents actin and myosin from interacting, thus preventing muscle contraction. By interacting with specialized receptors (ryanodine receptor channel) in the sarcoplasmic reticulum, dantrolene blocks the release of calcium ions. Calcium ions are critical for muscle contraction because they interact with the contractile filaments. The skeletal muscle contractile process cannot respond to stimulation even though conduction of impulses through the spinal cord and transmission across the neuromuscular junction are not affected. Dantrolene does not affect the nicotinic-muscle receptors or the NMJ. It is a direct-acting muscle relaxant because it acts within the muscle cell at calcium storage centers. Dantrolene dosing information is presented in Table 9:1 because it acts peripherally (outside the CNS) to produce skeletal muscle relaxation.
LO 9.4
LO 9.5
LO 9.6
C ENTRALLY A CTING S KELETAL M USCLE R ELAXANTS (SPASMOLYTICS) Spastic contraction of skeletal muscles may occur in response to overexertion, trauma, or nervous tension. Usually, the muscles undergoing spasm are limited to the area of trauma (neck, back, or calf). Reflexes within the spinal cord repeatedly stimulate the motor neurons so that localized muscle fibers contract intermittently. This perpetuates a cycle of irritation or inflammation within localized muscle areas. Drugs that inhibit or interrupt painful intermittent muscle contractions are called spasmolytics.
Clinical Indications
Mechanism of Action
Dantrolene is used in the treatment of malignant hyperthermia and spastic conditions. Muscle spasms associated with multiple sclerosis, cerebral palsy, and spinal cord injuries may reduce patients’ ability to function or perform activities required for daily living. Dantrolene, taken orally, relaxes spastic skeletal muscle and allows these individuals to make use of their residual motor function. In the prevention and treatment of malignant hyperthermia, dantrolene, given intravenously, interferes with the release of calcium in the sensitized muscles, reversing the biochemical crisis.
Drugs that relax skeletal muscle by a central mechanism depress reflex impulse conduction within the spinal cord. This change in conduction reduces the number of impulses available to produce muscle contraction. Centrally acting skeletal muscle relaxants do not alter the function of the nicotinic-muscle receptors or the skeletal muscle fibers. Some of these muscle relaxants interfere with select areas of the brain to interrupt the spasticity (reduce intraneuronal activity). Although all of the drugs listed in Table 9:2 relieve muscle spasticity, the benzodiazepines chlordiazepoxide (Librium) and diazepam (Valium) are primarily used as tranquilizers (antianxiety). These agents, which interact with GABA (gamma-aminobutyric acid), a neurotransmitter in the CNS, will be discussed in Chapter 12. See Figure 9.3 for sites of receptor interaction for centrally acting skeletal muscle relaxants. Many people encounter muscle relaxants as outpatient therapy for muscle strain and overexertion during leisure activities. Baclofen and tizanidine reduce the spasms that interfere with daily activities in patients with multiple sclerosis. Baclofen (Lioresal) is chemically related to a substance that naturally occurs in the brain (gamma-aminobutyric acid [GABA]). Like other centrally acting muscle relaxants, it inhibits reflexes at the spinal level. GABA is
Adverse Effects The most frequent adverse effects include dizziness, vomiting, fatigue, and weakness. Dantrolene has a potential for hepatotoxicity, which is indicated in a box warning in its instructions for use. As deaths have occurred due to hepatotoxicity, serum enzymes indicative of changes in liver function, aspartate amino transferase (AST/SGOT) and alanine amino transferase (ALT/SGPT), should be monitored frequently during dantrolene therapy. Contraindication to the use of dantrolene includes hepatitis and cirrhosis, as well as other active hepatic diseases. The longterm safety of dantrolene is being evaluated through its 122
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Table 9:2
Centrally Acting Skeletal Muscle Relaxants Drug (Trade Name)
Adult dose
Baclofen (Lioresal, Kemstro)
10–80 mg PO
Intrathecal baclofen therapy (ITB)
Individual titration to 300–800 mcg/day
Carisoprodol (Soma)
250–350 mg PO TID, and at bedtime
Chlordiazepoxide* (Librium)
2–10 mg PO TID, QID 2–20 mg IM, IV elderly 2–2.5 mg QD, BID
Chlorzoxazone (Parafon Forte DSC)
250–750 mg PO TID, QID
Cyclobenzaprine (Flexeril, Amrix)
5–10 mg PO TID
Diazepam* (Valium)
2–10 mg PO TID 5–10 mg IM**
Metaxalone (Skelaxin)
800 mg PO TID, QID
Methocarbamol (Robaxin)
1.0–1.5 g PO QID
Methocarbamol injection
1 or 2 vials (1000 mg/vial) IM, IV
Orphenadrine citrate
100 mg PO BID
Orphenadrine citrate (Banflex, Flexon, Norflex)
60 mg (1 ampule) IV, IM (every 12 hours as needed)**
Tizanidine (Zanaflex)
4–12 mg PO every 6–8 hours
*Although these drugs are used primarily as antianxiety agents, they are also skeletal muscle relaxants. **Should be changed to tablets as soon as the symptoms are relieved.
the principal inhibitory neurotransmitter within the brain. The GABA receptors are a superfamily of membranebound proteins (see Figure 9.3). When GABA binds to its GABAA and GABAB receptors, pores (ion channels) open through the lipid membrane, allowing passive movement of small ions. This ion movement changes the potential across the membrane, affecting conductivity of the cell. Benzodiazepines and baclofen bind with the GABA A and the GABA B receptors, respectively, and cause chloride ions (Cl−, negative ion) to move across the membrane into the cells, making the membrane hyperpolarized (can’t respond to stimulation). This decreases neuronal membrane “excitability.” GABA A receptors are continually active, so anything that interacts with them has continual response.
Baclofen is primarily used to relieve the symptoms of spasticity (flexor spasms, clonus, muscle rigidity) in patients with multiple sclerosis but also may be of value in patients with spinal cord injury resulting in severe spasticity. Through a different mechanism of action, tizanidine (Zanaflex) reduces spasticity by interacting with alpha-2-adrenergic receptors in the CNS. Neither of these drugs reverses the pathology of multiple sclerosis. Both are adjunct medications that improve the quality of life for many patients with spastic muscle conditions.
Route of Administration and Adverse Effects The centrally acting skeletal muscle relaxants may be administered orally or parenterally. Chapter 9 • Skeletal Muscle Relaxants
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Sites of Action of Centrally Acting Muscle Relaxants
Figure 9.3
Inhibitory interneuron Corticospinal pathway Motor neuron
␣2
Tizanidine
Baclofen ⴚ
ⴚ
GABAB GABA
ⴚ
␣2
GABAA ⴚ
Skeletal muscle
Benzodiazepines
Hyperpolarization
Action potential
Proposed sites of action of tizanidine (alpha-2), benzodiazepines (GABA A ), and baclofen (GABA B ) in the spinal cord. Neuronal endings in the inset are color coded to match the motor neuron, corticospinal pathway and inhibitory interneuron.
While most of the drugs in this group are taken as oral tablet or capsule formulations, certain drugs are available for parenteral administration for severe chronic conditions. Methocarbamol (Robaxin) is given intravenously for the treatment of tetanus. Baclofen (Lioresal ) is available for intrathecal injection. It is administered by a pump implanted under the skin in the area of the waistline. Candidates are thoroughly screened for compatibility to adapt to use of an implanted pump, but when selected, the drug delivery system is usually an alternative to otherwise destructive (ablative) neurosurgical procedures. To some degree, these drugs are metabolized in the liver and excreted in the urine. The most frequently reported adverse effects include blurred vision, dizziness, lethargy, and decreased mental alertness. The intensity of these effects may require patients to avoid driving or operating mechanical equipment. With large doses, skeletal muscle tone decreases, resulting in ataxia and hypotension. Tizanidine has the potential to decrease blood pressure because of its action on the sympathetic alpha-2 receptors. This may result in orthostatic hypotension in patients with multiple sclerosis. Prolonged use of diazepam and chlordiazepoxide may lead to dependency. Discontinuation of therapy in patients who have received any of these drugs for long 124
periods (chronically) must be gradual to avoid precipitating withdrawal symptoms. Usually, the dose is decreased over a 4- to 8-week period. Any of the muscle relaxants should be discontinued under medical supervision if a hypersensitivity reaction develops. However, this may require a gradual process of drug discontinuation to avoid the development of lifethreatening events. Special precautions must be taken when reducing the dose of baclofen during chronic therapy. If an adverse reaction occurs that prompts termination of baclofen therapy, the dose must be reduced gradually. Although not associated with dependence, hallucinations and/or seizures have been reported to occur when the drug was abruptly stopped. Abrupt discontinuation of intrathecal baclofen infusion has resulted in muscle rigidity, rebound spasticity, and, in some cases, organ failure and death. This is a black box warning for intrathecal baclofen use. Overdose of centrally acting skeletal muscle relaxants will produce symptoms of confusion, somnolence, and depression of vital functions including respiration, heart, and pulse rates. Coma may precede death if the patient does not receive adequate evaluation and treatment in time. There is no specific antidote for overdose associated with centrally acting muscle relaxants. The patient must be monitored for respiratory and
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Drugs that depress the CNS (alcohol, sedatives, and tranquilizers) or impair neuromuscular function potentiate the actions and adverse effects of all skeletal muscle relaxants.
drugs available for the relief of pain from muscle strain or overexertion, but these drugs do not act to inhibit or interrupt the muscle spasms. Muscle spasms may occur in individual muscle groups (leg, neck) producing feelings of pain or tightness in and around joints but also can cause generalized low-back pain. For the short-term treatment of muscle spasm or strain, carisoprodol (Soma) and cyclobenzaprine (Flexeril) are often the drugs of choice. Cyclobenzaprine also can be given before bedtime to aid with sleeping. Diazepam (Valium) is a drug well known by patients and physicians and may be selected to relieve low-back pain associated with muscle spasm. Diazepam is usually limited to one to two weeks because of its habit-forming potential.
Preferred Treatment for Selected Conditions
Disorders Associated with Chronic Spasticity
Surgical Relaxation
Chronic spasticity may be as mild as the feeling of stiffness or tightness of muscles, or it may be severe with painful uncontrollable spasms of the extremities, usually of the legs. Baclofen (Lioresal ) has been widely used for spasticity of any etiology (cause). Most studies indicate that it improves clonus, spasm frequency, and joint range of motion resulting in improved functional status for the patient. Patients with cerebral palsy and traumatic brain injury respond to dantrolene sodium (Dantrium), while tizanidine (Zanaflex) is used for the treatment of spasticity caused by multiple sclerosis and spinal cord injury.
cardiovascular activity while a clear airway is maintained and ventilation supported. In the event that hypotension develops, an IV infusion should be available for parenteral fluid therapy. There is a specific benzodiazepine antagonist, flumazenil (Romazicon), that can be used to reverse the depressive effects of chlordiazepoxide (Librium) or diazepam (Valium) overdose. This antagonist has no ability to reverse the depression associated with other centrally acting muscle relaxants.
Drug Interactions
The selection of a neuromuscular blocking drug for surgery depends on the time of onset and the duration, adverse effects, and reversibility (ability to remove the NMJ blockade) of the drug; the duration of the surgery; and the specific condition (weight, medical history, current conditions) of the patient.
Intubation None of the nondepolarizing blocking drugs equals the rapid onset and short duration of action of succinylcholine (Anectine). With a single 1-mg/kg dose of succinylcholine, tracheal relaxation occurs within 30 seconds and lasts up to 10 minutes. The nondepolarizing blocking drugs have an onset between 1.5 and 3 minutes and duration up to 90 minutes.
Relief of Back or Neck Pain There are many over-the-counter (nonsteroidal antiinflammatory drugs, Chapter 20) and prescription
Treatment of Malignant Hyperthermia Dantrolene (Dantrium) is the drug of choice for the treatment of malignant hyperthermia. Continuous parenteral administration of dantrolene proceeds until symptoms subside or the maximum cumulative dose of 10 mg/kg has been reached. If the physiologic and metabolic abnormalities reappear, the regimen may be repeated.
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Patient Administration and Monitoring When skeletal muscle relaxants are used in surgical settings, the potential for adverse effects may be minimized through close observation of the patient during recovery. Following diagnostic procedures or intubations under outpatient conditions, or chronic therapy for spastic muscle conditions, there is a greater likelihood that patients may experience adverse effects that could put them at risk for injury. For this reason patients should receive clear instructions about which adverse effects are worthy of physician notification. The centrally acting skeletal muscle relaxants may cause persistent drowsiness that interferes with mental alertness and concentration. For chronic spastic conditions, this effect is usually tolerable so the treatment schedule does not need to be interrupted. It should be noted that dose adjustment does not always mitigate the drowsy effect. Therefore, with short-term therapy of muscle strain, the patient may need to incorporate other solutions to circumvent the difficulties associated with drowsiness.
Skin rash, nasal congestion, persistent fever, or yellowish discoloration of the skin or eyes should be reported to the physician or clinic immediately for further evaluation.
Patient Instructions
Drugs in this class have been designated Food and Drug Administration (FDA) Pregnancy Category C or D. Safety for use during pregnancy has not been established through adequate and well-controlled studies in humans. All of these drugs, except diazepam, are category C because animal reproduction studies have shown an adverse effect on the fetus. Diazepam is category D because there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans. It is recommended that no drug should be administered during pregnancy unless it is clearly needed and the potential benefits to the patient outweigh the potential risks to the fetus.
The patient should be asked whether he or she performs tasks that require special equipment or machinery (sewing machines, motor vehicles) or coordination, focus, or physical dexterity (drill press, motor tools, assembly tools). Extra caution is needed, including identifying a coworker, on-site medical personnel, or a relative who is aware of the patient’s medication schedule. If necessary, alternate transportation when driving is required may be necessary until treatment is completed. Alcohol and other CNS depressant drugs should be avoided. This includes over-the-counter (OTC) medications that contain alcohol as a significant active ingredient. These drugs may potentiate poor coordination, drowsiness, and dizziness (postural hypotension).
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Dantrolene causes photosensitivity so prolonged exposure to sunlight should be avoided. Baclofen may cause nausea, headache, insomnia, and frequent or painful urination that should be reported to the physician for further evaluation. Tizanidine is available in capsules and tablets, but they are not interchangeable during the course of treatment. Patients should be reminded to continue the same formulation to avoid fluctuations in absorption. Capsules can be opened and sprinkled on applesauce to improve patient compliance when necessary; however, food does impact the bioavailability of tizanidine.
Use in Pregnancy
Patients who become pregnant or who expect to become pregnant during therapy should discuss with the physician the potential risks of therapy to the fetus.
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Chapter Review Understanding Terminology Answer the following questions. ___ 1. Differentiate between depolarizing blockers and nondepolarizing blockers. (LO 9.1) ___ 2. Explain the difference between peripheral skeletal muscle relaxants and centrally acting skeletal muscle relaxants. (LO 9.1, 9.4) ___ 3. Use the following terms in a short paragraph: fasciculation, hyperthermia, vagolytic, and vasodilator. (LO 9.6)
Acquiring Knowledge Answer the following questions. 1. What are the physiological events that precede skeletal muscle contraction? (LO 9.1) 2. What is a neuromuscular junction (NMJ)? (LO 9.1) 3. What sites are involved in the production of skeletal muscle relaxation? (LO 9.1, 9.4, 9.5) 4. What are the two types of neuromuscular blockers? How do they differ in their mechanism of action? (LO 9.1) 5. Why are neuromuscular blockers administered IV? (LO 9.2) 6. What adverse effects are produced by the neuromuscular blockers as a result of histamine release? (LO 9.6) 7. Describe the major toxicity associated with neuromuscular blockers and the antidote used. (LO 9.6) 8. How does dantrolene differ from neuromuscular blockers? (LO 9.1, 9.5) 9. What is the mechanism of action of centrally acting skeletal muscle relaxants? (LO 9.4) 10. When are centrally acting skeletal muscle relaxants used? (LO 9.2)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. As a health care worker in a busy health maintenance organization (HMO), you work with dozens of patients each day. You’ve noticed that each of the following three patients who were treated today has been prescribed a drug that could cause problems. For each patient, identify and explain the potential drug problem. a. Patient A came to the HMO this morning complaining of muscle pain following a back injury. He was prescribed the muscle relaxant cyclobenzaprine. Patient A is always joking with the nurses about how much he drinks. It’s clear that he takes several drinks of whiskey every day. (LO 9.6) b. Patient B came into the HMO last week with strep throat, for which he was prescribed streptomycin. Today, he’s complaining of neck and shoulder pain, which he attributes to driving his car for a total of 20 hours over the past 2 days. Patient B was prescribed metaxalone for the muscle pain. (LO 9.6) c. Patient C takes lidocaine for a heart arrhythmia. Yesterday, she injured herself doing calisthenics and spent a sleepless night in pain. Today, she visited the doctor and was prescribed methocarbamol to relax her sore muscles. (LO 9.6) 2. Assume that you work in a surgical unit where you coordinate patient medications. For each of the following patients, identify a potential drug problem and how it might be avoided. a. Jeri is about to have a type of orthopedic surgery that requires a muscle relaxant for best results. Jeri’s medical history indicates that she has asthma but is otherwise in good health. (LO 9.6)
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Chapter Review Continued b. Linda is scheduled for surgery on her back. Her surgeon is planning to give her succinylcholine to relax her muscles during the procedure. As far as the surgeon is aware, Linda is in great health other than the vertebrae that require surgery. Linda has confided in you, however, that she has bulimia, which you know can lead to electrolyte imbalance. (LO 9.6) c. Susan has knee surgery scheduled. A note on her chart indicates that she will be given succinylcholine during the operation to relax the muscles in her leg. Her chart also indicates that she takes digitalis for a heart problem. (LO 9.6)
Multiple Choice Use your critical-thinking skills to answer the following questions. 1. Which of the following is correct about skeletal muscle relaxants? (LO 9.1, 9.2, 9.6) A. intubation for emergency airway management may be accomplished quickly B. the clinical indication for these drugs is to prolong surgical procedures C. centrally acting skeletal muscle relaxants must inhibit nicotinic receptors D. their use is limited by the amount of histamine released from mast cells 2. Which of the following is correct about neuromuscular blocking drugs? (LO 9.1) A. the mechanism of action is the same as represented by dantrolene B. all of these drugs depolarize the muscle fiber before blockade occurs C. calcium ions are released from the storage sites D. there are two groups in this class: either depolarizing agents or nondepolarizing agents 3. Mivacurium and rocuronium are used to (LO 9.1, 9.2) A. relax muscle spasms from “week-end warrior” back strain B. block acetylcholine at the nicotinic-muscle (Nm) receptor C. stimulate the nicotinic-muscle (Nm) receptors D. produce muscle fasciculations in surgery 4. Succinylcholine is associated with which of the following actions? (LO 9.1) A. stimulation of the actin and myosin muscle fibrils directly B. liver damage because the drug is metabolized only by the liver C. peripheral neuromuscular receptor blockade after stimulating the Nm receptors D. longer duration of action than vecuronium 5. Centrally acting skeletal muscle relaxants (LO 9.1, 9.4, 9.5, 9.6) A. include dantrolene and cisatracurium B. inhibit or reduce activity within the spinal cord (intraneuronal), interrupting the central stimulus to muscle contraction C. can only be given parenterally D. cause systemic release of histamine, leading to hypotension 6. Which of the drugs is correctly paired with its effect? (LO 9.6) A. succinylcholine: life-threatening cardiac arrest in children B. tizanidine: hypertension and increased salivation C. cyclobenzaprine/metaxolol: antagonized by alcohol and sedatives D. vecuronium: increased blood pressure and heart rate 7. Skeletal muscle relaxants may alter control of respiration because (LO 9.3) A. the diaphragm is a skeletal muscle B. succinylcholine stimulates the respiratory centers in the brain
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C. like dantrolene, all muscle relaxants inhibit the action of norepinephrine at the neuromuscular junction D. relaxation of the muscles in the lower extremities pulls blood away from the lungs
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Select the drugs that decrease the effects of neuromuscular blockers. (LO 9.6) A. neomycin B. corticosteroids C. theophylline D. carbamazepine 2. Which of the following are ways in which skeletal muscles may be relaxed? (LO 9.1) A. blockage of conduction in the spinal cord B. inhibiting nerve transmission C. blockage of the NI receptors D. increasing ACH in the neuromuscular junction 3. Which of the following drugs are used in chronic spastic muscle disorders? (LO 9.5) A. metaxolone B. cyclobenzaprine C. baclofen D. methocarbamol 4. Select reasons for using muscle relaxers during surgical or diagnostic procedures. (LO 9.2) A. reduce muscle tear B. decrease body temperature C. potentiate vasodilators D. reduce muscle strain 5. What are the adverse effects of peripherally acting skeletal muscle relaxants? (LO 9.6) A. acidosis B. electrolyte imbalance C. decreased respiration D. shock
Sequencing Place the following steps of muscle contraction in the proper sequence. (LO 9.1) _______________
_______________
First
_______________
_______________ Last
ACH combines with Nm receptor ACH released in the neuromuscular synapse depolarization of muscle fibers impulse from CNS
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Chapter Review Continued Classification Put the drugs in their correct classification. (LO 9.5) Norflex
Robaxin
Soma
Zemuron
Nimbex
Flexeril Centrally acting
Peripherally acting
Matching Match the following terms with their correct definitions. (LO 9) a. fasciculation b. hyperthermia c. incompatibility d. myelin e. potentiates f. sarcolemma g. spasmolytics h. vagolytic 1. 2. 3. 4. 5. 6. 7. 8.
_____ _____ _____ _____ _____ _____ _____ _____
produces an action greater than the individual components produce alone fatty substance that covers and protects nerves increased body temperature thin membrane enclosing a striated, skeletal muscle fiber undesirable interaction between two drugs drugs that relieve, interrupt, or prevent muscle spasms inhibition of the vagus nerve twitching of muscle fibers
For interactive animations, videos, and assessment, visit:
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Chapter 10
Local A nesthetics DRUG CLASS AT A GLANCE OTC
YES
PRESCRIPTION
YES
SCHEDULED DRUGS NO Except for Cocaine CII FDA PREGNANCY CATEGORY
B, C
INDICATIONS Local or regional analgesia, anesthesia—spinal, local by Infiltration, or peripheral nerve block
KEY TERMS amide local anesthetic: anesthetic class that includes lidocaine, bupivicaine, and mepivicaine and has a moderate to long duration of action because metabolism occurs in the liver. cardiac arrhythmia: variation in the normal rhythm (motion) of the heart. caudal anesthesia: injection of a local anesthetic into the caudal or subcaudal spinal canal. cryoanesthesia: removing the sensation of touch or pain by applying extreme cold to the nerve endings. epidural anesthesia: injection of a local anesthetic into the extradural (the outermost part of the spinal canal) space. ester local anesthetic: anesthetic class that includes procaine, cocaine, benzocaine, and tetracaine; metabolism is primarily by plasma cholinesterases. general anesthetic drug that abolishes the response to pain by depressing the central nervous system (CNS) and producing loss of consciousness. hypersensitivity: exaggerated response such as rash, edema, or anaphylaxis that develops following exposure to certain drugs or chemicals. infiltration anesthesia: injection of a local anesthetic directly into the tissue. intradermal anesthesia: injection of a local anesthetic into the part of the skin called the dermis.
local anesthetic: drug that reduces response to pain by affecting nerve conduction. The action can be limited to an area of the body according to the site of administration. nerve conduction: transfer of impulses along a nerve by the movement of sodium and potassium ions. regional nerve block: also called nerve block; the injection of a local anesthetic near the nerve root. spinal anesthesia: injection of a local anesthetic into the subarachnoid space. topical application: placing a drug on the surface of the skin or a mucous membrane (for example, mouth, rectum). vasoconstriction: tightening or contraction of muscles (sphincters) in the blood vessels, which decreases blood flow through the vessels. vasodilation: relaxation of the muscles (sphincters) controlling blood vessel tone, which increases blood flow through the vessels.
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Learning Outcomes
After studying this chapter, you should be able to
10.3 identify which local anesthetics must be administered by injection.
10.1 describe how a local anesthetic works (mechanism of action).
10.4 describe the adverse effects associated with local anesthetic use.
10.2 explain how a local anesthetic can reduce pain without affecting the muscles that control posture.
10.5 identify two local anesthetic drugs that are important in the treatment of cardiac dysfunction because of their action on the heart (antiarrhythmic).
I ntroduction
Drugs may be used in many different ways to control pain. General anesthetics, to be discussed in Chapter 18, abolish the response to pain by depressing the CNS and producing loss of consciousness. However, it may be desirable to relieve pain without altering the alertness or mental function of the patient. To accomplish this, analgesics (opioid and nonopioid, Chapters 19 and 20) or local anesthetics may be used. The source and intensity of the pain determine which of these pharmacological agents is most useful to decrease the response to the painful stimuli. Local anesthetics, as their name suggests, produce a temporary loss of sensation or feeling in a confined area of the body.
LO 10.1 1
LO 10.2
M ECHANISM OF ACTION The most common clinical use of local anesthetics is to abolish painful stimulation prior to surgical, dental (tooth extraction), or obstetric (delivery) procedures. In addition, local anesthetics are ingredients in many overthe-counter (OTC) products for sunburn, insect bites, and hemorrhoids because these topical applications get local anesthetics to injured (pain-producing) nerve endings quickly. Local anesthetics abolish the response to pain because they inhibit sensory nerves that carry painful stimuli to the CNS. In particular, local anesthetics block nerve fiber conduction by acting directly on nerve membranes. Local anesthetics interact with nerve membranes to inhibit sodium ions from crossing the membranes. Neurons have sodium and potassium channels in their membranes. The sodium channel is actually a large protein (α subunit) in the membrane. Local anesthetics bind to this protein (α subunit) and effectively block the flow of sodium ions through the channel. This decreases sodium permeability across the membrane. If 132
sodium ion movement is inhibited, nerves cannot depolarize, and conduction of impulses along the nerves is blocked (Figure 10.1). Sodium influx (movement to the intracellular space) through these channels is necessary for the depolarization of nerve cell membranes and subsequent propagation of impulses along the nerve. When a nerve loses depolarization and the capacity to propagate an impulse, the individual loses sensation in the area supplied by the nerve. This blockade of nerve conduction is reversible, which means that when the local anesthetic is carried away from the nerve by the circulation, the action of the local anesthetic ends. The local anesthetic is then metabolized. Local anesthetics are valuable because they block sensory nerves at doses that do not inhibit motor nerve function. Peripheral nerve fibers and their neurons are classified as A, B, or C according to the diameter of the axon, amount of myelin covering the nerve, and conduction velocity (fast or slow). Sensory nerves carry impulses for pain, touch, warmth, and cold to the brain. The sensory and autonomic nerves (C fibers) are the first fibers to become blocked by local anesthetics because
Chapter 10 • Local Anesthetics
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Figure 10.1
Action of Local Anesthetics on Nerve Conduction
Extracellular Fluid
Extracellular Fluid
K+ channel
Na+ channel
Local Loc Lo L oca oc all anesthetic an ane a nes ne Large anions nss n that cannott escape celll
Intracellular Fluid conduction (a) Depolarization impulse con
Intracellular Fluid Local (b) L ocal anesthetic blockade of o sodium ion channel. No impulse im mpulse conduction.
(a) Depolarization—sodium ions (Na 1 ) move in and potassium ions (K 1 ) move out of the cells. (b) Local anesthetics enter the sodium channel and prevent sodium ion flow and depolarization.
these fibers are relatively small in diameter and unprotected by myelin sheaths (unmyelinated). Therefore, local anesthetics can easily penetrate the membranes and inhibit nerve conduction. In contrast, the motor nerves that supply skeletal muscle (A fibers) are the last fibers to be inhibited because motor nerves are large fibers with thick myelin coverings. The degree of nerve depression by local anesthetics is presented in Table 10:1. The importance of this is that pain fibers can be blocked without altering skeletal muscle function (for example, diaphragm, posture). In addition, the pain fibers surrounded by local anesthetic are the last to recover from local anesthetic blockade (good duration of action). LO 10.1 1
LO 10.3 3
LO 10.5
P HARMACOLOGY The most commonly used local anesthetics are listed in Table 10:2 on page 135. All of these agents produce adequate, controlled nerve block by inhibiting nerve conduction. Local anesthetics are weak bases that travel in the body as either uncharged or positively (+) charged molecules. Both forms are critical to local anesthetic activity. Which form is present depends on the environment (pH, lipid matrix, water solubility) surrounding the molecule. One form allows the drug to cross membranes and the other form allows the drug to interact with charged proteins in the plasma or at receptor sites. The uncharged local anesthetic (the more lipid-soluble form) allows the molecule to cross into the neuronal membrane (lipid matrix) and gain access to the sodium ion channel receptor
that lies inside the membrane. As it migrates to the area of the sodium ion channel, a more water-soluble area, the local anesthetic returns to its charged (+) form and binds with the sodium ion channel receptor. The intensity of receptor binding (affinity) influences the duration of local anesthetic nerve block. Local anesthetics differ in their duration of action, site of metabolism, and potency. There are two classes of local anesthetics: ester local anesthetics and amide local anesthetics. The ester local anesthetics have a short or moderate duration of action because they are metabolized by enzymes (cholinesterases) that are present in the blood and skin. Examples of ester local anesthetics are benzocaine, cocaine, cyclomethycaine, procaine, and tetracaine. Cocaine is the only naturally occurring drug among the local anesthetics. It is obtained from a plant in South and Central America. Cocaine, and the coca plant leaf, is classified as a Schedule II stimulant drug. It has a recognized medicinal use, but prescribing protocol and documentation must be followed (restricted drug). (See www.usdoj.gov/dea/pubs/scheduling.html for details.) Today all of the local anesthetics, even the recreational ones, are synthetically produced. Tetracaine is the only ester derivative that has a very long duration of action. Even though it is metabolized by plasma cholinesterases, tetracaine has a strong affinity for the sodium channel receptor that contributes to its significant duration of action, up to 3 to 5 hours. The amide local anesthetics are usually the longer-acting drugs because these agents must be metabolized in the liver. The amide group includes dibucaine, lidocaine, mepivacaine, ropivacaine, and prilocaine. Chapter 10 • Local Anesthetics
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Table 10:1
Nerve Fiber Characteristics and Order of Depression by Local Anesthetics Function
Diameter (µm)
Myelination
Conduction velocity (m/s)
Anesthetic block Sensitivity Onset
Postganglionic Pain
0.3–1.3 0.4–0.12
None None
0.7–2.3 0.5–2.3
++++ (most) Early ++++
Preganglionic autonomic
<3
Light
3–15
++++
Delta (Aδ)
Pain, temperature
2–5
Heavy
5–25
+++
Gamma (Aγ)
Muscle spindles
3–6
Heavy
15–30
++
Beta (Aβ)
Touch, pressure
5–12
Heavy
30–70
++
Alpha(Aα)
Proprioception, motor
12–20
Heavy
70–120
+ (least)
Fiber type Type C Sympathetic Dorsal root Type B
Type A
Procainamide is not routinely used as a local anesthetic. Its local anesthetic attribute acting on the conduction system within the heart makes it valuable as an antiarrhythmic drug. (See Chapter 23.) Potency is the ability of the anesthetic to produce a nerve block at a relatively low dose compared to other local anesthetics. The lipid solubility of the drug (uncharged form) directly contributes to its potency because it allows the molecules to gain quick access through the membrane and then on to the sodium ion channel. Tetracaine, bupivacaine, and ropivacaine are reported to be more than 15 times more potent than procaine. Other anesthetics like mepivacaine and lidocaine are 2 to 4 times more potent than procaine. If the site of administration is highly vascularized, the blood supply will pull anesthetic away from the site of action, reducing its effective duration of action. Often epinephrine is injected with the local anesthetic because epinephrine will constrict blood vessels and keep the local anesthetic at the site of action longer. LO 10.3
R OUTES OF A DMINISTRATION The duration of action and potency of local anesthetics determine which route of administration to employ. Local anesthetics are administered topically or by injection. Local anesthetics are poorly absorbed through an intact epidermis, but they are well absorbed from breaks or abrasions in the skin and from highly vascularized sites 134
Intermediate
Last
such as mucous membranes. Ester anesthetics, particularly those found in OTC preparations, readily are applied topically to the skin or mucous membranes. Topical application of local anesthetics also is known as surface anesthesia. Topical preparations are available as creams, lotions, ointments, sprays, suppositories, eyedrops, and lozenges. The most recent development in topical anesthesia includes combination local anesthetics applied to open and intact skin to reduce pain prior to suturing. The first available combination was TAC (tetracaine, adrenaline, cocaine). This preparation, although extremely effective, is being phased out by combinations that do not contain cocaine. LET (lidocaine, epinephrine, tetracaine) is not available commercially in this combination; it must be compounded as a liquid or gel by the pharmacist. EMLA (a eutectic mixture of local anesthetics) represents a major breakthrough in dermal anesthesia. Lidocaine and prilocaine are combined with a thickener and an emulsifier, applied as a thick layer to intact skin, and covered with clear plastic wrap to promote
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Table 10:2
Characteristics of Commonly Employed Local Anesthetics Drug (Trade Name)
Duration
Route
Preparations
Benzocaine (Dermoplast, Lanacane, Solarcaine, Sting-kill swabs)*
0.5–0.75 hr
Topical
5% cream, ointment 2–20% spray
Cocaine**
0.25–0.75 hr
Topical
1–4% solution
Chloroprocaine (Nesacaine)
0.25–0.50 hr
Injection
1–3% solution
Procaine (Novocaine) infiltration
0.25–1.0 hr
Injection
1–2% and 10% solutions
Tetracaine (Pontocaine)
2–3 hr
Injection
0.2, 0.3, and 1% solutions
Tetracaine (Pontocaine Viractin)*
—
Topical
1% cream, 5% ointment
Bupivacaine (Marcaine)
2–4 hr
Injection
0.25–0.75% solution
Dibucaine (Nupercainal )*
0.5 hr
Topical
1% ointment
Lidocaine (Xylocaine)
0.5–1 hr
Injection
2 and 4% solution
Lidocaine (Lidoderm)
3 hr
Topical
5% lidocaine patch
Lidocaine (Bactine spray)** (Solarcaine, Aloe extra burn relief )
0.5 hr
Topical
2% jelly, 2.5 and 5% ointment
Mepivacaine (Carbocaine)
0.75–1.5 hr
Injection
1 and 2% solutions
Prilocaine (Citanest)
0.5–1.5 hr
Injection
1–4% solutions
Ropivacaine (Naropin)
2–6 hr
Injection
0.5–2% solution
EMLA (lidocaine, prilocaine)
0.5–2 hr
Topical
2.5% of each anesthetic in thick layer
LET (lidocaine, epinephrine, tetracaine)
Not established
Topical
4% lidocaine, 0.5% tetracaine, 1:2000 epinephrine
Septocaine (articaine and epinephrine)
Varies with dose
Injection
4% articaine, 1:100,000 epinephrine
TAC (tetracaine, adrenaline, cocaine)
Not established
Topical
0.5% tetracaine, 11.8% cocaine, 1:2000 epinephrine
Ethyl chloride
Minutes
Topical
Spray
Benzyl alcohol, phenol, camphor, menthol
Minutes
Topical
Spray, lotions, creams
GumEase®
Minutes
Topical
Dental mouthpiece
Esters
Amides
Combinations
Other surface cooling agents ***
*Over-the-counter preparations. **Federally restricted drug, Schedule II. ***Decreases surface temperature.
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penetration through the skin. The breakthrough is that this preparation permits much higher concentrations of local anesthetic to be absorbed topically than possible by individual surface preparations. EMLA also can be used to anesthetize skin before intramuscular injections, venipuncture, and procedures such as biopsies. Parenteral administration of local anesthetics (injection) may involve several different sites, including under the skin (intradermal anesthesia) and into the spaces around the spinal cord (spinal, epidural, or caudal anesthesia). Figure 10.2 illustrates where local anesthetics are administered along the spinal cord to produce different levels of anesthesia. When local anesthetics are administered extradurally, it is called an epidural or caudal blockade. Injections around peripheral nerves are called perineural or paravertebral blockade. Injection into the subarachnoid space (cerebrospinal fluid) is a spinal blockade. The choice of anesthetic is usually based on the duration of action required. The long-acting, potent amide anesthetics are administered primarily by injection. Intravenous injection of a local anesthetic into a specific region, usually an arm or leg isolated by a tourniquet, for short surgical procedures is referred to as a Bier block. There are combination preparations containing the amide lidocaine that are applied topically to facilitate suturing or injection of additional anesthetic.
Note to the Health Care Professional Local anesthetic solutions occasionally contain epinephrine to counteract the vasodilation that occurs with local anesthetics. Always read the contents of the bottle before administering a local anesthetic. Anesthetic agents come in a variety of containers and packaging. It is crucial to confirm the correct anesthetic and concentration and whether additional active agents are being delivered with the local anesthetic. Preparations containing epinephrine generally have epinephrine printed in red ink for easy visibility and a red top on multipleuse vials, as shown in Figure 10.3. Local anesthetic preparations that contain epinephrine should not be used for nerve block in the areas of the fingers, toes, ears, nose, or penis. In such areas, epinephrine may produce intense vasoconstriction, leading to ischemia and gangrene. Epinephrine also is contraindicated in conjunction with general anesthetics that increase cardiac excitability (arrhythmogenic).
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Infiltration anesthesia is the most commonly used local anesthetic technique. Infiltrative anesthesia is achieved by injecting a local anesthetic directly into the tissue. The extent of anesthesia is determined by the depth of tissue penetrated—that is, the tissue infiltrated. The duration of action following infiltration anesthesia for several injectable local anesthetics is presented in Table 10:2. Lidocaine, in a 1% concentration, is most commonly used for this type of infiltration. However, when increased procedure times are expected, anesthetics with a longer duration of action are substituted. When these local anesthetics are administered in combination with epinephrine (usually 1:200,000 dilution), the duration of anesthesia may be doubled. For example, prilocaine (0.5–1.5 hr), mepivacaine (0.75–1.5 hr), dibucaine (3–4 hr), and bupivacaine (2–4 hr) administered with epinephrine may have their duration of action extended up to 6 hours. The addition of epinephrine retards transport of the local anesthetic away from the site of injection and the neuron continues to be bathed in local anesthetic. A regional nerve block is achieved by injecting an anesthetic solution around a nerve root so that the whole area the nerve goes to becomes anesthetized. Regional blocks allow a smaller amount of anesthetic to be used, while anesthetizing larger surface areas and reducing the risk of systemic toxicity. Amide-type anesthetics, usually 2% lidocaine, are used most often for regional blocks. Regional nerve blocks are used in the management of pain associated with the lower back, neck, sciatica (from a herniated disc), reflex sympathetic dystrophy (a complex regional pain syndrome), shingles, cancer, and painful peripheral vascular disease. It also can be used in the treatment of migraine headaches. Local anesthesia can be produced without the use of local anesthetic drugs. Cryoanesthesia refers to the external application of cold to the skin to produce numbness. Ice or ethyl chloride, a refrigerant spray, applied directly to the site for 30–60 seconds, provides superficial short-duration anesthesia that may be adequate for removing superficial lesions. This application is particularly useful in children or adults who have a fear of needles. Cryoanesthesia also is used with several skin laser machines that quickly spray a little coolant before each laser pulse to take away the sting of the laser. GumEase® is a new easy-to-use disposable device for oral cavity pain management. A regional pain block is achieved by the local application of extreme cold to the maxillofacial nerves. The chilled nerve fibers can no longer transmit pain impulses to the brain. GumEase® resembles a teething ring containing a cryoanesthetic compound that sits comfortably within the patient’s mouth. Patients can apply the device postoperatively as needed.
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Figure 10.2
Spinal Cord and Nerve Roots
C1 Dural sheath Subarachnoid space
C7
Cervical spinal nerves Subarachnoid space in spinal canal Spinal nerve block T12 Base of spinal cord Thoracic spinal nerves
T12
L1
Paravertebral nerve block
Dura Epidural space
L2
Cauda equina
L3
Epidural or peridural nerve block
L4 L5
Lumbar spinal nerves
Cauda equina
S1 Filum terminale
L5
S2
Epidural space in caudal canal Terminal filum S5
Sacral spinal nerves
Caudal block
Col (a)
(b)
Schematic diagram with typical sites of local anesthetic injection in and around the spinal canal.
Figure 10.3 Safety Alert: Identification LO 10.4 4
LO 10.5
A DVERSE E FFECTS
Red cap and red label for lidocaine containing epinephrine.
Local anesthetics are administered to produce a pharmacological response in a well-defined area of the body. However, a local anesthetic occasionally is absorbed into the blood from the site of administration and, passing through the circulation, it affects tissues and organs along the way. The most frequent and serious side effects from systemic absorption of a local anesthetic involve the blood vessels, heart, and brain. When combination products are being used, additional adverse effects may occur from the adjunct medication, usually epinephrine (vasoconstriction, hypertension). Chapter 10 • Local Anesthetics
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Vascular Effects
Hypersentivity and Allergic Effects
Cocaine was the first local anesthetic to be discovered. Although it has potent local anesthetic activity, cocaine cannot be used by injection because it produces intense vasoconstriction. Cocaine interferes with the sympathetic nervous system and the blood vessels. Today, cocaine is used topically in surgical procedures on the eyes and nasal mucosa because its vasoconstrictor action decreases operative bleeding and improves surgical visualization. Additional information on cocaine is presented in Chapter 15, Psychotomimetic Drugs of Abuse. All of the other local anesthetics used today produce vasodilation; procaine, in particular, produces a marked dilation of blood vessels, which may lead to hypotension. Except for cocaine, toxic levels of the local anesthetics relax vascular smooth muscle and produce significant hypotension. These effects may lead to cardiovascular collapse.
Allergic contact dermatitis and delayed swelling at the site of administration are rare. Clinical signs include pruritus, urticaria, facial swelling, wheezing, dyspnea, cyanosis, laryngeal edema, nausea, vomiting, and abdominal cramping. The ester local anesthetics are more often identified when an individual develops an allergic or hypersensitivity reaction after repeated exposure to the drug. Allergic reaction to the esters is usually due to sensitivity to the metabolite para-amino benzoic acid (PABA). While cross-reactivity exists among ester anesthetics, it does not appear to occur between ester and amide anesthetics. If an individual develops an allergic reaction to ester anesthetics, all ester anesthetics should be avoided and an amide local anesthetic selected for use. These reactions are not dose related; they are idiosyncratic. A patient who is allergic to an ester-type anesthetic may react to preservatives (sodium metabisulfate) in multiple-dose vials of amide anesthetics. Single-dose vials are preservative-free and may be used in patients with a known hypersensitivity reaction to the ester anesthetics.
Cardiac Effects Local anesthetics depress the function of the cardiac conduction system and the myocardium. Usually, these drugs produce a negative chronotropic (bradycardia) and a negative ionotropic response on the heart. In toxic doses, local anesthetics produce cardiac arrhythmias. It must be pointed out that in therapeutic (subtoxic) doses, two of the local anesthetics can be administered intravenously to correct certain cardiac arrhythmias. Lidocaine and procainamide are unique drugs because at very low doses they can protect cardiac function, while at toxic doses they inhibit normal cardiac function. The role of lidocaine and procainamide in the therapy of cardiac arrhythmias is discussed further in Chapter 23.
Central Nervous System Effects All of the local anesthetics can affect the CNS. In large or toxic doses, the local anesthetics can cross the bloodbrain barrier and initially stimulate the cerebral cortex. The symptoms of cortical stimulation are nervousness, excitation, tremors, and convulsions. In general, the more potent the anesthetic, the more readily convulsions occur. As the concentration of local anesthetic increases in the brain, all areas of the CNS become depressed. Finally, at toxic levels, local anesthetics produce coma and death due to total depression of the CNS. Treatment of a local anesthetic overdose when CNS excitation is present includes barbiturates and diazepam (Valium). Once total CNS depression has occurred, the only available treatment is supportive restoration of breathing and blood pressure. In particular, artificial respiration is the essential feature of treatment in the late phase of anesthetic intoxication. 138
LO 10.4
C LINICAL A PPLICATIONS AND P REFERRED T REATMENT Local anesthetics are vital to cutaneous surgery and dental procedures. They are used by medical personnel and nonmedical consumers for a variety of indications. These drugs are readily available, effective, relatively inexpensive, and easy to administer either alone or as adjunct medications to other procedures. Topical application of local anesthetics relieves pain and itching associated with sunburn, skin abrasions, insect bites and other allergic reactions, and skin eruptions from chicken pox. Rectal suppositories relieve the pain produced by hemorrhoids. Introduction of a patch containing local anesthetic has use in dental procedures to reduce the pain associated with anesthetic injection and to alleviate painful discomfort following Herpes zoster neuralgia. Especially to facilitate procedures in children, a lidocaine/tetracaine patch can be applied 20 to 30 minutes prior to venipuncture or IV cannulation. A patch containing 5% lidocaine (Lidoderm) is the first FDA-approved medication indicated to relieve the pain of postherpetic neuralgia. Injection of local anesthetics, especially the long-acting amides, is used for surgical, suturing, and obstetrical procedures (epidural, caudal, spinal anesthesia) where the patients remain conscious. Bupivacaine, chloroprocaine, etidodaine, lidocaine, mepivacaine, and ropivacaine, with or without
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epinephrine, are the most frequently used local anesthetics for infiltration, peripheral nerve block, or caudal and lumbar block. Procaine can be used for infiltration and nerve block of short duration. Dentistry is one of the most frequent clinical applications of local anesthetics. Articaine, bupivacaine, chloroprocaine, lidocaine, and prilocaine are most frequently used in dental procedures. Unless otherwise indicated, a vasoconstrictor such as epinephrine is usually preferred to minimize the need for reinjection.
Cautions and Contraindications Local anesthetics are used in pregnant women as needed (see Patient Administration and Monitoring for more information). The physiology of pregnancy does alter the dynamics of the local anesthetic. During pregnancy, hepatic blood is increased and plasma protein binding is decreased, making the amide local anesthetics more available for metabolism and excretion. This results in an increased amide local anesthetic clearance from the body. In the presence of kidney failure, the amide anesthetic clearance is decreased. In hepatic failure, amide metabolites may accumulate. These patients require special attention during a monitored recovery period. Local anesthetics may release histamine from mast cells located at the site of injection, producing a rash and local itching typical of a histaminic response of Lewis (see Chapter 31). Occasionally, a patient is hypersensitive to local anesthetics. If a rash or edema occurs, the drug should be stopped immediately. Hypersensitivity may develop to ester local anesthetics when they are used frequently. When a complete medical history is available, the anesthesia team can avoid use of the offending drugs. Unfortunately, local anesthetics abound in OTC preparations and the hypersensitivity may result from prolonged use or abuse of topical preparations. For this reason, topical preparations (creams, ointments, and sprays) should never be used continually for prolonged periods. If hypersensitivity develops and a local anesthetic is required, amide derivatives may be substituted usually without fear of enhancing the allergic response. Topical application of local anesthetics for sunburn, skin abrasions, and corneal wounds may result in systemic drug levels and toxic responses. When the skin is damaged or opened, local anesthetics can easily reach the blood vessels, and when the pain is intense, patients usually apply local anesthetics several times a day. It is not unusual for a patient to develop hypotension, tremors, and convulsions due to overdose of a local anesthetic.
Special Considerations When administering a local anesthetic parenterally, monitor cardiovascular and respiratory vital signs after each injection. Restlessness, dizziness, blurred vision, and slurred speech may be early signs of CNS toxicity. Always inject an anesthetic slowly to avoid systemic reactions. Debilitated patients, as well as elderly and pediatric patients, may require reduced doses because these patients are often more susceptible to the actions of local anesthetics. Local anesthetic solutions that contain a vasoconstrictor must be used with extreme caution in patients who have a medical history of hypertension, cerebral vascular insufficiency, heart block, thyrotoxicosis, or diabetes. (Review the effects of sympathomimetic drugs on the cardiovascular and metabolic systems.)
Black Box Warning As a class of drugs, the local anesthetics are closely monitored when administered parenterally by physicians and dentists. Among all the available local anesthetics, only one is associated with a significant warning for use above 0.5% concentration. Obstetrical anesthesia: The 0.75% concentration of bupivacaine is not recommended for obstetrical anesthesia because cardiac arrest with difficult resuscitation or death has occurred following rapid intravenous injection to pregnant women. The concentration is indicated only for lengthy nonobstetrical surgery requiring profound muscle relaxation.
Overdose of topical anesthetics may result in the same life-threatening response as from parentally administered drugs. If convulsions occur, it is an acute emergency. There is no specific antidote. Supportive treatment includes maintaining a clear airway and assisting ventilation with oxygen. If convulsions persist, an ultrashort-acting barbiturate or benzodiazepine may be given parenterally. Intravenous fluids and vasopressors are used when the circulation and organ perfusion are compromised.
Drug Interactions Local anesthetics are not involved in many drug interactions. However, they may enhance hypotension that occurs with antihypertensive drugs and muscle relaxants. Drugs that directly relax skeletal muscle are enhanced by the use of local anesthetics introduced into the spinal canal. Local anesthetics may increase the release of histamine even when they are being used to relieve an allergic reaction, and this histamine release will only worsen the clinical condition. Chapter 10 • Local Anesthetics
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Procaine has been shown to inhibit the action of sulfonamide antibiotics. Procaine is metabolized to p-aminobenzoic acid, which competes with the sulfonamide for the bacterial site of action. Patients who have experienced a hypersensitivity reaction to an ester local anesthetic are more likely to experience a similar reaction if exposed to other ester local anesthetics. Generally, it is advisable to
use an amide local anesthetic as an alternative; rarely, cross-sensitivity with lidocaine has been reported. Sedatives may interact with spinal local anesthetics to potentiate CNS depression. Combination anesthetics that contain epinephrine may produce an increased sympathetic response and sustained hypertension when a patient is taking tricyclic antidepressants or MAO inhibitors.
Patient Administration and Monitoring Assuming the patient is closely monitored during the procedure, adverse effects may be minimized when local anesthetics are used in operating and emergency rooms. The use of anesthetics in dental procedures as well as available products for self-medication exposes the general population to greater risk of experiencing certain adverse effects. Patients should be instructed about predictable local anesthetic action that could cause problems—namely, loss of sensory perception and motor function.
Patient Instructions The patient should be advised that loss of sensory perception and motor function may persist for a short time. This means the anesthetized region cannot respond to hot or cold stimuli or to deep scratching. Avoid exposing the skin or mucous membranes (gums) to extreme temperature foods for at least 1 hour or until full pain sensation has returned. Following topical application to relieve sore throat, the patient should not eat for 1 hour. Since sensation is impaired, there is always the danger that the patient may aspirate food particles. Dental anesthesia will more than likely leave the patient with numbness of the tongue, lip, and/or oral mucosa for up to 1 hour after the procedure. The patient should be alerted to the possible annoying effect of accidentally biting the lips or cheeks during this time. Since pressure perception is impaired, the patient may unconsciously bite extremely hard and find terrific pain and blisters after the anesthetic has subsided. It is advisable that while the tissue is still anesthetized, the patient should not eat or chew gum because of the potential for aspiration to occur.
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Notify the Physician Patients routinely use OTC products containing local anesthetics for a multitude of conditions from sore throat to vaginal and/or rectal itch. While the patient may have 10 preparations for use on different body parts, they all probably contain a local anesthetic. Moreover, these are the type of products used by the more sensitive patients such as the elderly and children. The patient should be reminded that any time the skin or mucous membrane is broken, as in sunburn, minor scratches, or irritated mucosa, the local anesthetic may be more well absorbed. Development of mental confusion and changes in pulse or respiration should be reported to the physician for further evaluation. A small percentage of people are allergic (hypersensitive) to the para-aminobenzoic acid metabolites of procaine and tetracaine. Local swelling, edema, itching, difficulty in breathing, and bronchospasm may indicate hypersensitivity to the anesthetic. If such symptoms occur while using any local anesthetic, the patient should notify the doctor immediately and discontinue the anesthetic.
Use in Pregnancy Drugs in this class have been designated Food and Drug Administration (FDA) Pregnancy Category B and C. The safety of local anesthetic use in pregnancy has not been established through research in humans; however, the shortterm exposure to these drugs during labor and delivery limits the potential risk to the patient and newborn. Adverse effects observed in the newborn, primarily depression of the CNS and cardiovascular tone, quickly reverse once exposure is terminated. The degree of depression is related to the type and amount of local anesthetic administered to the mother.
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Chapter Review Understanding Terminology Answer the following questions. 1. Differentiate between local and general anesthetics. (LO 10.1, 10.2) 2. Explain the difference between vasodilation and vasoconstriction. (LO 10.1, 10.2) Match the definition in the left column with the appropriate term in the right column. ___ 3. An exaggerated response (such as rash or edema) to a local anesthetic. (LO 10.4)
a. caudal anesthesia
___ 4. Placing a drug on the surface of the skin or a mucous membrane. (LO 10.4)
c. hypersensitivity
___ 5. Injection of a local anesthetic into the subarachnoid space. (LO 10.4)
e. intradermal anesthesia
___ 6. Injection of a local anesthetic into the extradural space. (LO 10.4) ___ 7.
b. epidural anesthesia
d. infiltration anesthesia
f. spinal anesthesia g. topical application
Injection of a local anesthetic into the caudal or subcaudal canal. (LO 10.4)
___ 8. Injection of a local anesthetic directly into the tissue. (LO 10.4) ___ 9. Injection of a local anesthetic under the skin. (LO 10.4)
Acquiring Knowledge Answer the following questions. 1. Explain how local anesthetics block the response to pain. (LO 10.1) 2. Which nerves are first affected when a local anesthetic is applied? What is the order of depression? (LO 10.1, 10.2) 3. What are two classes of local anesthetics? How do they differ? (LO 10.1, 10.4) 4. What body systems are mainly affected by systemic absorption of local anesthetics? (LO 10.4) 5. What are the adverse effects of local anesthetics on the heart? (LO 10.4) 6. What are the adverse effects of local anesthetics on the CNS? (LO 10.4) 7. Compare the effects of cocaine and procaine on blood pressure. (LO 10.4) 8. Why is epinephrine added to some local anesthetic preparations? (LO 10.1, 10.4) 9. What precautions are associated with the use of local anesthetics and vasoconstrictors? (LO 10.4) 10. What drugs may interact with local anesthetics to produce undesirable effects? (LO 10.4)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. Mrs. Brown was rushed to the emergency room by ambulance after her husband found her lying on the kitchen floor having convulsions. She has no previous history of convulsions and appeared to be in good health earlier in the day. You notice that Mrs. Brown has abrasions on her lower right arm, which
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Chapter Review Continued her husband says she received when she fell to the pavement when bicycling yesterday. He says that she has been self-medicating with an over-the-counter ointment for pain ever since. What do you think caused Mrs. Brown’s convulsions? (LO 10.4) Use the PDR® or F&C to answer the following questions. 2. Lidocaine is available in a topical viscous solution preparation. List the strength, peak effect and duration times, and the indications. (LO 10.1) 3. Bupivacaine is available in the following strengths; 0.25%, 0.5%, and 0.75%. This is commonly used for obstetrical lumbar epidural. One strength is contraindicated for this procedure. Which strength is contraindicated and why? (LO 10.4) Use F&C to answer the following question. 4. You are reviewing the medication orders for the cataract extraction procedures scheduled for the next day. The anesthetic that will be used is proparacaine (Opthetic ). What dosing would you expect to find? (LO 10.1, 10.4)
Multiple Choice Questions Use your critical-thinking skills to answer the following questions. 1. Which of the following is a significant therapeutic effect of the ester local anesthetics? (LO 10.1, 10.4) A. increase in diastolic blood pressure B. itching at the site of application C. loss of sensation to touch and warmth D. depression of motor neuron function 2. The duration of action of a single administration of amide local anesthetic dibucaine or bupivacaine (LO 10.1) A. is shorter than the duration of action of procaine B. is longer than 30 minutes C. is decreased by adding epinephrine to the local anesthetic D. depends on the amount of cholinesterase in the blood 3. Any local anesthetic decreases the response to pain (mechanism of action) (LO10.1) A. by binding and inactivating membrane ion channels that affect sodium movement B. after the drug reacts with receptors in the brain C. by removing sodium and potassium ions from the cells D. by increasing nerve conduction of painful stimuli 4. Local anesthetic therapeutic effect to block nerve conduction (LO 10.1) A. only happens if the local anesthetic is injected B. causes irritation and redness at the site of application C. reversibly binds chloride and magnesium ions in the skin D. can be achieved with topical creams, sprays, and ointments. 5. Local anesthetics other than cocaine (LO 10.4) A. are weak acids B. are Schedule restricted drugs because of their similarity to cocaine C. can only be metabolized by the liver to remove their effect D. produce vasodilation
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6. Which of the following is a local anesthetic? (LO 10.1) A. ropivacaine B. norepinephrine C. succcinylcholine D. adrenaline 7. Which of the following local anesthetics is used to treat cardiac arrhythmias? (LO 10.5) A. prilocaine B. lidocaine C. tetracaine D. cocaine 8. Which of the following statements is correct about the local anesthetic? (LO 10.3) A. topical application of procaine establishes a caudal nerve block B. tetracaine can only be administered by injection C. injection of bupivacaine at the spinal nerve root such as at T4 establishes a regional nerve block D. articaine is administered with epinephrine to enhance vasodilation
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Which of the following anesthetics are given by injection? (LO 10.3) A. dibucaine B. ropivacaine C. Pontocaine D. benzocaine 2. Lidocaine can be given to treat which conditions? (LO 10.5) A. sunburns B. cardiac arrhythmias C. vasoconstriction D. insect bites 3. The mechanism of action for local anesthetics includes (LO 10.1) A. altering skeletal muscle function B. blocking sensory nerve conduction C. inhibiting sodium ion movement D. depolarizing nerves 4. Select the adverse effects of local anesthetics. (LO 10.4) A. anesthetization of the skin B. inhibition of sensory nerves C. convulsions D. bradycardia 5. What are the early signs of CNS toxicity from injected local anesthetics? (LO 10.4) A. restlessness B. blurred vision C. slurred speech D. dizziness
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Chapter Review Continued Sequencing Place the following in order from longest duration of action to shortest duration of action. (LO 10.1) _________________
_________________
_________________
_________________
Longest
Shortest
Pontocaine Nesacaine Duranest EMLA
Classification Place each drug under the appropriate route of administration. (LO 10.3) Septocaine
Nupercainal
Dermoplast
Novocain
TAC
Carbocaine
Naropin
Ropivacaine
Injectable
Topical
Documentation Using the prescription below, answer the following questions. (LO 10.3) a. b. c. d.
What is the route of administration for this drug? Has the doctor provided enough information for you to determine a route of administration? If the prescription was to be injected, what dosage strengths are available? What is the duration of action for the injectable form of this drug?
Day Surgery Practice RX 12345 Main Avenue Anytown, USA 12345 931-555-1000 NAME::
Holly Fields
DATE:
ADDRESS: RX
Pontocaine
Sig:
Use as directed
Dr. Warren Fisk Substitution Permitted
DEA #:
144
M.D.
M.D. Dispense as written
REFILL:
NR
1
2
3
4
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Labeling Fill in the missing labels. (LO 10.3)
Spinal nerve block T12
Paravertebral nerve block
L1
L2 L3
L4
Epidural or peridural nerve block L5
S1 S2
Caudal block
For interactive animations, videos, and assessment, visit:
www.mcgrawhillconnect.com Chapter 10 • Chapter Review
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3
CHAPTER 11
CHAPTER 19
Introduction to the Central Nervous System 146
Opioid Analgesics
PART
P harmacology of the C entral N ervous S ystem 268
CHAPTER 20 CHAPTER 12 Sedative-Hypnotic Drugs and Alcohol 157
Nonopioid Analgesics, Nonsteroidal Antiinflammatories, and Antigout Drugs 292
CHAPTER 13 Antipsychotic and Antianxiety Drugs
173
CHAPTER 14 Antidepressants, Psychomotor Stimulants, and Lithium 188
CHAPTER 15 Psychotomimetic Drugs of Abuse 203
CHAPTER 16 Antiepileptic Drugs 216
CHAPTER 17 Antiparkinson Drugs 229
CHAPTER 18 General Anesthetics 243 147
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Chapter 11
I ntroduction to the C entral N ervous S ystem KEY TERMS basal ganglia: a group of cell bodies (gray matter) within the white matter of the cerebrum that helps control body movement. cerebellum: part of the brain that coordinates body movements and posture and helps maintain body equilibrium. cerebral cortex: uppermost layers of the cerebrum involved in sensory perception, voluntary motor control, and all higher intellectual abilities. cerebrum: largest and uppermost part of the brain that is divided into right and left cerebral hemispheres. electroencephalogram (EEG): a surface recording of the electrical brain. hypothalamus: part of the diencephalon that regulates functions such as body temperature, water balance, appetite, and the pituitary gland. limbic system: neural pathway connecting different brain areas involved in regulation of behavior and emotion. medulla oblongata: lower part of the brainstem that controls cardiac, vasomotor, and respiratory functions. pons: part of the brainstem that serves as a relay station for nerve fibers traveling to other brain areas; also involved in sensory and motor functions. reticular formation: network of nerve fibers that travel throughout the central nervous system that regulates the level of wakefulness. thalamus: uppermost part of the diencephalon that regulates sensory and motor impulses traveling to and from the cerebral cortex.
Learning Outcomes
After studying this chapter, you should be able to 11.1 describe the main anatomic structures of the brain, the difference between gray and white matter, and the functions of the cerebral cortical lobes and basal ganglia.
11.3 explain the major function of the cerebellum. 11.4 explain the basic structure and function of the spinal cord. 11.5 describe the reticular formation and the limbic system and discuss the importance of each.
11.2 list the main parts of the brainstem and discuss the functions associated with each part.
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Introduction
The central nervous system (CNS) is composed of the brain and spinal cord. The primary functions of the CNS are to coordinate and control the activity of other body systems. Distinct nerve pathways in the CNS interconnect different areas of the brain that serve the same function. Neurons in these pathways are linked together by synapses. These neurons release neurotransmitters, which regulate transmission across the synapses. In this way, nerve impulses are conducted to different areas of the brain to influence the levels of activity. There are a significant number of neurotransmitters—including acetylcholine (ACH), norepinephrine (NE), dopamine, and serotonin—that have been identified in the brain. Some mental illnesses and pathological conditions are associated with abnormal changes in the amount or activity of a specific neurotransmitter. Many of the drugs that act on the CNS do so by affecting neurotransmitter concentrations and activity. While there are a large number of different neurotransmitters in the brain, the function and activities of each are similar to the functions of the neurons and nerve endings (adrenergic, cholinergic) previously discussed with the autonomic nervous system. Generally, a neuron releases one specific type of neurotransmitter that crosses the synapse and binds to its receptor located on the dendrites of the next adjoining neuron. Neurotransmitters can be either excitatory or inhibitory. Excitatory receptor stimulation generates action potentials that flow along the nerve axon to stimulate release of the neurotransmitter from the nerve endings of that neuron . . . and so on. Inhibitory neurotransmitters produce actions on the next adjoining neuron that inhibit the generation of action potentials. In this manner, neurotransmitters function to either generate nerve impulses that transmit information among the different brain centers or inhibit the flow of action potentials, which reduces neural activity. The released neurotransmitters are inactivated by metabolism or reuptake into their respective nerve endings. Figure 11.1 illustrates the synaptic connections of a typical brain neuron. In the CNS, neurons having the same functions are generally grouped together. The cell bodies of these neurons form control centers for the various body functions. Consequently, the CNS is anatomically divided into different structural and functional components. In order to understand how drugs affect the CNS, the main structures and functions of the CNS will be reviewed.
LO 11.1
S TRUCTURAL AND F UNCTIONAL F EATURES OF THE B RAIN The brain may be divided into the cerebrum, diencephalon, brainstem, and cerebellum. The basic anatomy and physiology of these structures will be briefly reviewed in order to provide background for the site and action of drugs acting on the central nervous system.
Cerebrum The cerebrum is the largest and uppermost part of the brain. All of the higher intellectual abilities of human beings are controlled by the cerebrum. Anatomically, the cerebrum is divided into right and left cerebral
hemispheres. Each hemisphere is composed of an outer layer of gray matter, the cerebral cortex, composed of nerve cell bodies, and an inner layer of white matter composed of nerve cell axons.
Cerebral Cortex The cerebral cortex contains the cell bodies of neurons (gray matter) that perceive and are actively involved with all conscious activities of the mind and intellect. All sensory sensations are perceived and all voluntary muscle movements of the body are initiated from the cortex. The cortex is subdivided into four main lobes. The cortical lobes are named after the skull bones under which they are located and include the frontal, Chapter 11 • Introduction to the Central Nervous System
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Figure 11.1
Illustration of the Synaptic Connections Between Brain Neurons
NT
NT Receptors
Action potential
Synapse
NT Receptors Nerve axon Nerve ending Dendrites with neurotransmitter (NT) receptor sites NT Nerve endings from one neuron release neurotransmitter (NT), which crosses synapse to bind to NT receptor (R) on dendrites of next neuron. Receptor stimulation generates an action potential that travels down the nerve axon to stimulate the release of NT from nerve endings.
parietal, temporal, and occipital lobes ( Figure 11.2). The frontal lobe is responsible for control of muscle movement, the motor components of speech, abstract thinking, and problem-solving activity. The parietal lobe is responsible for the sensory sensations of touch, pressure, pain, temperature, and vibration. The temporal lobes are involved in hearing, learning, memory, and language functions. The occipital lobes function in vision. There are neural connections between the lobes and each area of the brain that allow communication, coordination, and integration of neural function. The lobes of the cerebral cortex are shown in Figure 11.2. An electroencephalogram (EEG) is a recording of the electrical activity of the brain. The EEG is useful in diagnosing various brain disorders and in evaluating the stages of sleep. Figure 11.2 Lobes of the Cerebral Cortex Parietal lobe
Frontal lobe
Occipital lobe
The white matter of the cerebrum is composed of the myelinated axons of neurons. The axons conduct nerve impulses to and from the cerebral cortex to different areas of the nervous system. Within the white matter of the cerebrum is a group of cell bodies (gray matter) known as the basal ganglia.
Basal Ganglia The basal ganglia receive nerve input from the cerebral cortex, cerebellum, and other areas of the brain involved in body movement. The main function of the basal ganglia is to help coordinate and regulate muscular activity. The basal ganglia are also referred to as the extrapyramidal system (EPS). The pyramidal system consists of all the descending motor nerves that come from the frontal lobes and travel to all the skeletal muscles. The pyramidal system controls the activity of skeletal muscle while the extrapyramidal system helps regulate skeletal muscle activity. Degeneration of neurons within the basal ganglia that produce dopamine are the cause of Parkinson’s disease. Deficiencies of dopamine cause the tremors, muscular rigidity, and problems with posture and movement that are the major symptoms of this condition. The antiparkinson drugs are discussed in Chapter 17. LO 11.2
DIENCEPHALON AND BRAINSTEM Temporal lobe Each lobe is named according to the skull bone under which it is located.
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The diencephalon includes the thalamus and hypothalamus which are located directly below the cerebral hemispheres. The brainstem includes the midbrain, pons, and medulla oblongata which are located below
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the diencephalons and that is continuous with the spinal cord. These structures are illustrated in Figure 11.3
Thalamus The thalamus receives and evaluates almost all of the sensory nerve impulses from peripheral sensory receptors before passing this information to the parietal lobe of the cerebral cortex. These include nerve impulses for pain, touch, temperature, and other sensory information. The thalamus also is involved in motor control by integrating motor information from the basal ganglia and cerebellum.
Hypothalamus
Medulla Oblongata The medulla oblongata lies just above the spinal cord. Within the medulla oblongata are the three vital centers: cardiac (heart), vasomotor (blood pressure), and respiratory (breathing). Normal functioning of the vital centers is essential for life support. Injury to the medulla oblongata frequently results in death. Overdose with drugs, such as alcohol or barbiturates, causes death by depressing the function of the vital centers. Several important reflexes also are regulated by the medulla oblongata, including swallowing, coughing, vomiting, and gagging. LO 11.3
Located below the thalamus, is the hypothalamus. The hypothalamus controls many body functions including temperature, water balance, appetite, sleep, the autonomic nervous system, and certain emotional or behavioral responses. The pituitary gland is attached to the hypothalamus. Referred to as the master gland of the body, the pituitary gland regulates the function of many other endocrine glands. The pituitary gland and the pharmacology of the endocrine system will be considered in Chapter 35.
Pons Located below the hypothalamus, the pons is involved in both sensory and motor functions. It receives input from the reticular formation and has a role in the regulation of respiration and sleep. The pons also serves as a relay station for nerve fibers traveling to other brain areas.
Figure 11.3 Brain Section Showing the Structures of the Diencephalon and Brainstem from the Thalamus to the Medulla
CEREBELLUM The cerebellum lies behind the brainstem and below the cerebrum. The cerebellum is attached to the pons, medulla oblongata, and other areas of the brainstem. The major functions of the cerebellum, which is divided into right and left cerebellar hemispheres, are to coordinate body movements and posture and to help maintain body equilibrium. Disorders of the cerebellum can cause disturbances of posture and movement, tremors, muscle weakness, and decreased tendon reflexes. Drugs that depress the cerebellum, such as alcohol, usually decrease body coordination and reaction time. LO 11.4
SPINAL CORD The spinal cord is a collection of nerve axons that travel to and from the brain. Nerve axons traveling from the peripheral parts of the body (skin, muscle, visceral organs) to the brain (afferent neurons) carry sensory information (touch, pain, hot and cold sensations, etc.). Nerve axons traveling from the brain to the peripheral organs and skeletal muscle (efferent neurons) carry motor impulses that direct organ activity and muscle movement. Drugs that act on the spinal cord, mainly anesthetics, analgesics, and muscle relaxants, are primarily used to alter pain sensation and reduce the tone and activity of skeletal muscle. LO 11.5
F UNCTIONAL C OMPONENTS Thalamus Midbrain (tegmentum) Pons Medulla oblongata
Midbrain (tectum) Cerebellum
In addition to the main anatomical parts of the brain just described, several other functional neuronal pathways are located within the brain. These components form diffuse nerve networks that connect many different areas of the brain together; the reticular formation and the limbic system are two such components. Chapter 11 • Introduction to the Central Nervous System
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Reticular Formation The reticular formation is a network of nerve fibers that travel throughout the brain and spinal cord. The reticular formation has synaptic connections with many different brain areas that are involved, for example, in motor control, cardiovascular control, sleep, and wakefulness. It is composed of two types of fibers: excitatory and inhibitory. When the excitatory fibers are stimulated by various external stimuli (noise, bright light, or danger), the degree of alertness increases, preparing the body for a situation that requires action. The excitatory fibers are usually referred to as the reticular activating system (RAS). When there is a lack of external stimuli, the inhibitory fibers become more active, decreasing the activity of this system and, consequently, the degree of arousal or alertness. This decrease normally occurs during periods of rest or sleep. Consequently, the reticular formation helps regulate the degree of alertness or wakefulness of the nervous system. The reticular formation is sensitive to the effects of many drugs. Alcohol, barbiturates, and other depressant drugs decrease its activity and may induce sleep or unconsciousness. Stimulants, such as amphetamines and caffeine, increase the activity of the reticular formation and are usually used or abused to stimulate the CNS and maintain wakefulness.
Limbic System The limbic system refers to a collection of neurons and brain areas that form a specific interconnecting neural pathway. Major components of the limbic system include the amygdala, hippocampus, and cingulate gyrus (Figure 11.4). These structures are located around the hypothalamus and lower portions of the cerebrum. The limbic system is involved with the emotional and behavioral responses of the body associated with reward
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and punishment, sexual behavior, anger or rage, fear, and anxiety; therefore, the limbic system is important to mental health. Certain areas of the limbic system are referred to as pleasure or reward centers. Activities that activate these areas provide gratification and these activities are likely to be repeated. Certain addictions such as smoking and drug abuse affect these centers. Other areas of the limbic system are associated with unpleasant sensations or feelings and activities that affect these areas are likely to be avoided. Specific drug classes, such as the antianxiety agents and some antidepressant drugs, exert a selective inhibitory effect on the limbic system and are useful for the treatment of certain behavioral and emotional disorders. The area of pharmacology that deals with drugs affecting the CNS is known as neuropharmacology. In the following chapters, the major classes of drugs that affect the CNS will be considered.
Figure 11.4 Major Anatomic Structures Forming the Limbic System Medial prefrontal cortex Fornix Corpus callosum Thalamic nuclei
Cingulate gyrus Orbitofrontal cortex Basal nuclei
Mammillary body
Hippocampus
Amygdala Temporal lobe
The structures of the limbic system are shown in violet.
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Chapter Review Understanding Terminology Match the description in the left column with the appropriate part of the brain in the right column. (LO 11.1, 11.2) ___ 1. Coordinates body movements and posture, helps maintain equilibrium.
a. basal ganglia
___ 2. Group of cell bodies within the cerebrum.
c. cerebral cortex
___ 3. Composed of myelinated axons that conduct nerve impulses to and from the cerebral cortex.
d. cerebral white matter
___ 4. Largest and uppermost part of the brain. ___ 5. Regulates sensory impulses traveling to the cortex.
b. cerebellum
e. cerebrum f. medulla oblongata g. thalamus
___ 6. Controls cardiac, vasomotor, and respiratory functions. ___ 7. Controls the body’s higher intellectual and voluntary activities.
Acquiring Knowledge Answer the following questions. 1. What are the main functions of the central nervous system? (LO 11.1) 2. List some of the neurotransmitters found in the brain. What is the function of a neurotransmitter? (LO 11.1) 3. Where are the basal ganglia located and what function is associated with them? (LO 11.1) 4. List the main structures in the brainstem. (LO 11.2) 5. List the main functions of the hypothalamus and the medulla oblongata. (LO 11.2) 6. What are the main functions of the cerebellum and spinal cord? (LO 11.3, 11.4) 7. What is the reticular formation? How does it function to regulate the level of wakefulness or arousal? (LO 11.5) 8. What is the limbic system? What functions are associated with this system? (LO 11.5)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. As patient liaison in a large metropolitan hospital, one of your duties is to educate patients and their families about their illnesses and treatments. For the following cases, explain why the patients present with the signs and symptoms that they do. (LO 11.2) a. Patient A, a 16-year-old female, took an overdose of one of the barbiturate drugs and was brought to the emergency room (ER) by her parents. She presents in the ER with a heart rate of 45, blood pressure of 85 over 55, and slow, irregular breathing. b. Patient B took an accidental overdose of an amphetamine and presents at the ER in a state of excitability, with rapid breathing, heart palpitations, excessive perspiration, anxiety, and irritability. c. Patient C is an 18-year-old male who has had a few beers once or twice a month since he turned 18. He has never consumed hard liquor until tonight, when he attended a party where he participated in a drinking contest. At that time, he drank several ounces of whiskey in a few minutes. He passed out and could not be awakened. A sober friend brought him to the ER, still unconscious. His heart rate is slow, his blood pressure down, and his breathing is irregular.
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Chapter Review Continued 2. Assume a patient of the doctor you assist has Parkinson’s disease. He and his wife think his problem is in his muscles. Explain to them what is really affected and why he has the symptoms he does. (LO 11.1)
Multiple Choice Use your critical-thinking skills to answer the following questions. 1. Select the structure located within the brainstem (LO 11.1) A. hypothalamus B. cerebral cortex C. cerebral white matter D. medulla oblongata 2. Body temperature, appetite, and water balance are regulated by the (LO 11.2) A. pons B. cerebellum C. medulla oblongata D. hypothalamus 3. Sensory sensations such as touch, pressure, and pain are perceived in the (LO 11.1) A. frontal lobe B. temporal lobe C. parietal lobe D. occipital lobe 4. The “vital centers” are regulated by the (LO 11.2) A. hypothalamus B. reticular formation C. cerebral cortex D. medulla oblongata 5. The area of the brain that is involved with emotional and behavioral responses is the (LO 11.5) A. reticular formation B. limbic system C. basal ganglia D. occipital lobe
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Select the main parts of the brainstem. (LO 11.2) A. spinal cord B. thalamus C. cerebral medulla D. medulla oblongata 2. Choose the main functions of the cerebellum. (LO 11.3) A. equilibrium B. body posture C. temperature control D. water balance
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3. Which of the following is not a function of the spinal cord? (LO 11.4) A. sensation of hot B. recognition of pain C. direct organ activity D. regulation of breathing 4. Select the area or areas of the central nervous system involved with emotional and behavioral responses. (LO 11.2, 11.5) A. hypothalamus B. reticular formation C. limbic system D. pons 5. The basal ganglia control which of the following body functions? (LO 11.1) A. regulating the vomiting reflex B. regulating body temperature C. regulating muscular activity D. regulating sensory impulses
Sequencing Place the following in order from the uppermost section of the central nervous system to the lowermost. (LO 11.1, 11.2, 11.4) ____________________
____________________
____________________
Upper
____________________ Lower
cerebrum cerebellum medulla oblongata spinal cord
Classification Place the following body functions under the part of the brain that controls them. (LO 11.1, 11.2) breathing
water balance
memory
appetite
sleep
blood pressure
regulation of swallowing reflex
language
abstract thought
Cerebrum
Hypothalamus
Medulla oblongata
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Chapter Review Continued Labeling Fill in the missing labels. (LO 11.5)
For interactive animations, videos, and assessment, visit:
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C hapter 12
S edative H ypnotic D rugs and A lcohol DRUG CLASS AT A GLANCE OTC
Alcohol, ramelteon
PRESCRIPTION
YES
SCHEDULED DRUGS
YES
FDA PREGNANCY B, C, D, X CATEGORY
KEY TERMS automatism: drug-induced confusion that can cause increased drug consumption. barbiturate: CNS depressant drug possessing the barbituric acid ring structure. benzodiazepine: class of drugs used to treat anxiety and sleep disorders. GABA: gamma-aminobutyric acid, an inhibitory neurotransmitter in the CNS. hypnotic: drug used to induce and maintain sleep.
INDICATIONS Sedation and hypnosis
nonbarbiturate: refers to sedative-hypnotic drugs that do not possess the barbituric acid structure, such as benzodiazepines and related drugs. NREM sleep: stages of sleep characterized by nonrapid eye movement (NREM). REM sleep: stage of sleep characterized by rapid eye movement (REM) and dreaming. sedative: drug used to produce mental relaxation and to reduce the desire for physical activity.
Learning Outcomes
After studying this chapter, you should be able to 12.1 describe the stages of the sleep cycle and the main characteristics of each stage.
12.4 explain the mechanism of action of the benzodiazepine hypnotics and the pharmacokinetic differences between the short-acting and longer-acting drugs.
12.2 explain the mechanism of action of the sedative-hypnotic drugs in relationship to their actions with GABA and the chloride ion channel.
12.5 explain the mechanism of action of eszopiclone, zaleplon, and zolpidem and the advantages of these drugs over barbiturates and benzodiazepines.
12.3 describe the adverse effects of barbiturates, the addiction liability, and treatment of barbiturate overdose.
12.6 describe the major pharmacologic effects and adverse reactions of ethyl alcohol.
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Introduction
The central nervous system coordinates and controls the activity of all other body systems. As a result, anything that directly affects the CNS ultimately influences the overall function of the body. With increased CNS stimulation, a person responds by becoming more alert, anxious, and occasionally more irritable. Excessive CNS stimulation can cause convulsions or various forms of abnormal behavior. Abuse of amphetamines or cocaine can cause these effects. In contrast, depression of the CNS reduces both physical and mental activity. Excessive CNS depression can produce unconsciousness, coma, and death. CNS depression is frequently related to abuse of barbiturates and alcohol. Sedatives and hypnotics are used therapeutically to decrease CNS activity. The same drugs are used for both sedation and hypnosis; the difference is that the sedative dosage is lower. Sedatives are used to reduce the desire for physical activity. Usually a sedative will be prescribed after a heart attack or some other condition when overexertion may be harmful. Various emotional or medical situations can cause anxiety and tension to interfere with sleep. When an individual is unable to sleep (insomnia), excessive tiredness can contribute to greater anxiety and make any situation worse. In this instance, hypnotic drugs may be prescribed to induce and maintain sleep (Figure 12.1). Use of hypnotics should be intermittent and only when really needed. Regular use should be limited to 2 to 4 weeks at any one time. Tolerance develops to the hypnotics and effectiveness usually decreases with prolonged and continuous use. Several different drug classes are used as sedatives and hypnotics. These drugs are chemically classified as the barbiturates and the nonbarbiturates. The barbiturates are rarely used today as sedatives or hypnotics because of their high abuse potential and addiction liability. The nonbarbiturates include the benzodiazepines and several chemically unrelated hypnotics classified as miscellaneous drugs. Before discussing the pharmacology of the sedatives and hypnotics, a brief review of the sleep cycle will be presented.
Figure 12.1
The Emotional Reaction to the Gradual Depression of the Central Nervous System
Unem Stress ploym Marr iage ent s
am Ex
Bills
Old a
Work
ge
Tense
Effects of drug:
Calm
Drowsy
Tranquilizing
Sedatlve
CNS stimulation
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Asleep
Hypnotic
Gradual depression of CNS
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Figure 12.2
Brain Waves Recorded from an Electroencephalogram
Alpha ( )
Beta ( )
Theta ( )
Delta ( )
(a)
(b)
1 second
LO 12.1
S LEEP C YCLE Although sedative-hypnotic drugs are primarily used to induce and maintain sleep, many of these drugs alter the normal sleep cycle. The normal sleep cycle is divided into two different states: nonrapid eye movement (NREM) and rapid eye movement (REM) sleep. NREM has been divided into four stages. Progression from stage 1 to stage 4 is characterized by a deeper level of sleep and usually takes 60 to 90 minutes. After stage 4, individuals normally enter REM sleep for approximately 20 minutes. Dreaming usually occurs during REM sleep. After a period of REM sleep, individuals return to NREM sleep and repeat the cycle. Depending on the length of sleep, most individuals usually go through four to six sleep cycles per night. The different stages of sleep produce brain waves that can be identified from an electroencephalogram (EEG) and are useful in evaluating sleep disorders. Examples of brain waves recorded from an EEG are shown in Figure 12.2.
Stage 1 NREM Individuals are somewhat aware of surroundings but relaxed; the eyes are usually closed. Alpha waves predominate in this stage. Stage 1 normally lasts a few minutes and occupies 4 to 5 percent of total sleep time.
Stage 2 NREM Individuals become unaware of surroundings but can be easily awakened. Brain waves in stage 2 are increased in
amplitude compared to alpha waves in stage 1 but occur at a lower frequency. Stage 2 occupies about 50 percent of total sleep time.
Stages 3 and 4 NREM Stages 3 and 4 are referred to as “slow-wave sleep” because of the high-amplitude, low-frequency delta waves observed on the electroencephalogram (EEG). These are deeper stages of sleep and are particularly important for physical rest and restoration. They occupy approximately 20 to 25 percent of total sleep time. One of the effects that occurs with aging is a reduction in the amount of time spent in slow-wave sleep. This is one of the factors that can contribute to insomnia and problems with sleeping as individuals age.
REM The REM stage is characterized by bursts of rapid eye movement (REM), increased autonomic activity, and dreaming. It is believed to be essential for mental restoration. During REM sleep, daily events are reviewed and information is integrated into memory. REM sleep appears to be an active state of sleep; the EEG records beta-type waves that are similar to those of the waking state. However, individuals are harder to awaken from REM sleep than other sleep stages. For this reason REM sleep is also referred to as “paradoxical sleep.” REM sleep occupies about 20 to 25 percent of total sleep time. The sequence of brain waves during a normal sleep cycle is shown in Figure 12.3.
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Figure 12.3 EEG Patterns Observed During the Stages of Sleep
Sleep stages reverse through 4-3-2-1 before REM sleep begins Increasing depth of sleep
Stage 1
2 3 Non-REM sleep
4 REM sleep
LO 12.2
M ECHANISM OF ACTION OF S EDATIVE -H YPNOTIC D RUGS The activity of the brain is in large part dependent upon the action of various neurotransmitters. Each neurotransmitter is released from a specific nerve ending and functions to either stimulate or inhibit neuronal activity. One of the most important inhibitory neurotransmitters is gamma-aminobutyric acid (GABA). GABA accounts for approximately 50 percent of the inhibitory activity of the brain and spinal cord. Neuronal function is in large part also dependent upon the action of various ions such as sodium (Na+), potassium (K+), and chloride (CL−). Each of these ions moves in through (influx) or out of (efflux) the neuronal membrane through specific ion channels. Nerve action potentials are generated when Na+ ions influx through sodium channels to depolarize (inside more positive) the nerve membrane. Nerve action potentials are inhibited when Cl− ions influx through chloride channels to hyperpolarize (inside more negative) the nerve membrane. The neurotransmitter that regulates the chloride channel is GABA. The chloride channel is composed of five subunits: two alpha, two beta, and one gamma. These form a circular channel that when open allows the Cl− ions to pass 160
through the nerve membrane into the neuron. GABA binds to a specific site on the channel referred to as the GABA A receptor. When GABA binds to the GABA A receptor, the channel opens and Cl− ions influx into the nerve, causing hyperpolarization. This reduces generation of action potentials and inhibits neuronal activity. The chloride channel also contains additional receptor sites for barbiturates, benzodiazepines, and other hypnotic drugs. These hypnotic drugs increase GABA A receptor-mediated chloride influx by binding to their specific drug receptor sites on the chloride channel. Barbiturates prolong the duration of channel opening and increase Cl− ion influx. Barbiturates also are believed to have additional inhibitory actions both related and unrelated to the chloride channel. The benzodiazepines bind to their receptors, named the benzodiazepine receptors (BZD receptors), and increase the activity of GABA by increasing the frequency of chloride channel opening. Drugs such as zaleplon, zolpidem, and eszopiclone demonstrate a more selective binding to a subunit of the benzodiazepine receptor (referred to as the BZD1 receptor). This selective binding offers certain hypnotic advantages over barbiturate and benzodiazepine drugs. Each of these drug classes acts to facilitate the inhibitory actions of GABA to increase chloride ion influx. A diagram of the chloride ion channel with its binding sites for GABA and related drugs is illustrated in Figure 12.4. LO 12.3
BARBITURATE S EDATIVES AND H YPNOTICS The barbiturates are among the oldest of drugs in the sedative-hypnotic class. These drugs have a number of disadvantages and their use as hypnotics has been mostly replaced by newer and more effective drugs. All of the barbiturates are structurally similar to the parent compound, barbituric acid. The barbiturates produce a dosedependent depression of the CNS. At higher doses, all barbiturates can produce general anesthesia. Because these drugs are still available and indicated for conditions other than hypnosis, they will be briefly discussed. However, emphasis in this chapter will be to present the general pharmacology of the barbiturate drug class. Barbiturates that are used as anticonvulsants and general anesthetics will be discussed in Chapters 16 and 18, respectively.
Mechanism of Action At lower doses, the barbiturates bind to their drug receptors on the GABA receptor-mediated chloride ion channel. This increases the influx of chloride ions and results in hyperpolarization of nerve membranes, as
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Figure 12.4 Diagrammatic Representation of the Chloride Ion Channel Extracellular Cl⫺
GABA 
GABA 
␣
␥
␣
Benzodiazepines Flumazenil Zolpidem
Barbiturates Ion channel Intracellular
This diagram shows the location of receptor sites for GABA and the various hypnotic drugs. The hypnotic drugs enhance the inhibitory actions of GABA to increase the influx of chloride ions and inhibit neuronal activity.
previously discussed. In the reticular formation, these inhibitory actions decrease the activity of the reticular activating system (RAS) and promote either sedation or sleep, depending on the dosage. At higher doses, barbiturates also cause a general depression of the entire CNS that is similar to the actions of the general anesthetics (Chapter 18). This action of the barbiturates is not well understood but may be related to the ability of the barbiturates to dissolve in neuronal membranes, where they interfere with the normal function and movement of ions that regulate neuronal excitability and the release of excitatory neurotransmitters. When used as hypnotics the barbiturates usually increase stage 2 sleep but decrease slow-wave sleep (stages 3 and 4). In addition, barbiturates suppress REM sleep. When barbiturates are discontinued, patients often spend excess time in REM sleep during the next night or two so as to make up for the lost REM sleep (REM rebound). During the rebound period, there is increased dreaming that may cause restlessness, anxiety, and nightmares. The disruption of the normal sleep cycle caused by barbiturates is another reason why they are no longer recommended as hypnotics.
Pharmacokinetics The barbiturates are well absorbed following oral administration. Once in the circulation, these drugs
are readily distributed to all tissues. Symptoms of CNS depression occur within 30 to 60 minutes following oral administration. The drug microsomal metabolizing system (DMMS) in the liver is responsible for inactivation of the barbiturates. When taken regularly for more than several days, barbiturates begin to induce the microsomal enzymes. Enzyme induction refers to an increase in the amount of drug-metabolizing enzymes in the liver. Enzyme induction results in faster metabolism of the barbiturate. Consequently, the duration of action is decreased, and patients must take larger doses of the drug to attain the same pharmacological effect as before. When this occurs, patients are said to have developed drug tolerance. When enzyme induction of the metabolizing enzymes occurs, all of the drug-metabolizing enzymes are increased. Therefore, any other drugs taken at the same time also are metabolized faster. This effect is responsible for a number of drug interactions. Barbiturates are eliminated mostly by the urinary system.
Barbiturate Drugs Phenobarbital (Luminal) Phenobarbital is classified as a long-acting barbiturate, with a duration of 6 to 12 hours. When used as a hypnotic, phenobarbital may produce a “hangover effect,” where individuals feel drugged the next morning because of the prolonged duration of action. Phenobarbital also is used as an anticonvulsant drug in the treatment of epilepsy (Chapter 16).
Pentobarbital (Nembutal) Pentobarbital is classified as an intermediate-acting sedative-hypnotic, with a duration of 4 to 6 hours.
Amobarbital (Amytal) Amobarbital is similar to pentobarbital. In addition, both of these barbiturates can be used parenterally to stop convulsions.
Secobarbital (Seconal) Secobarbital is a short-acting hypnotic, with a duration of 2 to 4 hours. The hypnotic indication is for individuals who have difficulty falling asleep but not staying asleep.
Adverse Effects The adverse effects associated with the barbiturates are an extension of their therapeutic action (CNS depression). Drowsiness, dry mouth, lethargy, and incoordination occur most frequently. These adverse effects Chapter 12 • Sedative-Hypnotic Drugs and Alcohol
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are more annoying than harmful. However, depressed reflexes and impaired judgment may contribute to serious accidents if patients operate motor vehicles or heavy machinery while taking these drugs. Elderly patients are particularly sensitive to CNS side effects, especially mental confusion and memory difficulties. When memory is impaired due to CNS depression, patients may not remember if the drug was taken. As a result, they may retake the drug repeatedly and experience an overdose. This phenomenon, known as automatism, may lead to drug intoxication and death. Mild overdosage of the sedative-hypnotic drugs resembles alcohol intoxication (inebriation). Slurred speech, ataxia, impaired judgment, irritability, and psychological disturbances are characteristic of intoxication.
leading to irregular breathing and hypoxia (cyanosis). Severe intoxication with the barbiturates usually leads to coma, respiratory depression, and death. There is no antidote for barbiturate overdose. Treatment of comatose patients includes supportive therapy to maintain respiration and blood pressure. Endotracheal intubation and artificial respiration may be employed. Also, sympathomimetic (alpha-adrenergic) drugs and intravenous (IV) fluids may be administered to elevate blood pressure. Osmotic diuretics administered intravenously may stimulate urine production so that renal excretion of the drug can occur. In addition, alkalinization of the urine (pH 7.0 or above) will increase the excretion of the more acidic barbiturates, like phenobarbital. Hemodialysis or peritoneal dialysis may be required when kidney function is depressed.
Addiction Liability
Cautions and Contraindications
Prolonged and excessive use of barbiturates results in tolerance and physical dependence. In addition, crosstolerance (resistance) develops to the depressant effects of other CNS depressants, such as alcohol and benzodiazepines. This occurs because the mechanism of action of all these drugs involves the interaction with GABA and the chloride ion channel. The mechanism for the production of tolerance and dependency has not yet been clearly determined. Physical dependency usually develops when greater therapeutic dosages are taken on a regular basis for more than 1 to 2 months. Once physical dependence develops, the drug must be used continuously to avoid the onset of withdrawal symptoms. Withdrawal symptoms include anxiety, insomnia, cramping, tremors, paranoid behavior, delirium, and convulsions. The abstinence syndrome (withdrawal) associated with barbiturates is especially dangerous. If withdrawal is not conducted within an adequately supervised medical center, convulsive seizures and death may occur.
The barbiturates are the drugs frequently used for attempted suicide. Because of their rapid action, the short-acting drugs are particularly dangerous. Many patients die before medical treatment can be administered. To prevent hospitalized patients from hoarding medication, always make sure they have swallowed the sedative-hypnotic at the scheduled time. Never leave pills lying on the nightstand to be taken at discretion. The barbiturates are contraindicated in patients who have acute intermittent porphyria. In this condition, an overproduction of hemoglobin (porphyrin) precursors accumulate in the liver. Sedative-hypnotics like the barbiturates stimulate and increase the production of porphyrins that can precipitate an attack (may cause nerve damage, pain, paralysis) in patients prone to this condition.
Barbiturate Poisoning Overdose with the barbiturates results in extensive cardiovascular and CNS depression. In large doses, these drugs depress all brain activity, including that of the vital centers in the medulla oblongata. Inhibition of vasomotor centers in the medulla oblongata removes sympathetic control of the blood vessels, and dilation of the blood vessels contributes to the production of hypotension and shock. In the presence of hypotension, kidney function decreases. There is little or no production of urine (oliguria or anuria) to remove the toxic products from the body. Medullary respiratory centers also are depressed, 162
Pregnancy The barbiturates are designated as Food and Drug Administration (FDA) Pregnancy Category D, which indicates that they can cause harmful effects to the fetus. Consequently, these drugs should be avoided during pregnancy.
Drug Interactions Sedative-hypnotic drugs undergo extensive interactions with other drugs. Sedative-hypnotic agents will potentiate the actions of other CNS depressant drugs, leading to greater CNS and respiratory depression. Sedativehypnotics and alcohol can be a deadly combination and should never be taken together. Because barbiturates cause enzyme induction, other drugs may be metabolized more rapidly in their presence. This rapid metabolism results in a decreased pharmacological effect of drugs such as the oral anticoagulants and oral contraceptives. Most of the sedative-hypnotic drugs
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are bound to plasma proteins; therefore, they compete with other drugs for protein-binding sites. Proteinbinding displacement usually leads to a potentiation of the pharmacological effect of the drug displaced. LO 12.4
B ENZODIAZEPINES The benzodiazepines are a class of drugs widely used in the treatment of anxiety. They are commonly referred to as the antianxiety drugs. The general pharmacology of the benzodiazepines is presented more fully in Chapter 13. However, in addition to producing antianxiety effects, all benzodiazepines exert sedative, hypnotic, muscle relaxant, and anticonvulsant effects. These pharmacologic actions are useful in a variety of clinical conditions. Several benzodiazepines are marketed specifically as hypnotics, and these drugs are included in this chapter (Table 12:1). The benzodiazepines are also the drugs preferred for producing sedation. However, the preferred benzodiazepines for sedation—diazepam, alprazolam, and lorazepam—are more frequently used to treat anxiety and are discussed in Chapter 13.
Mechanism of Action The benzodiazepines produce sedative and hypnotic effects by increasing the inhibitory activity of gammaaminobutyric acid (GABA). As previously discussed, the
benzodiazepines bind to their drug receptor sites (BZD receptors) that are in close relationship to the GABA receptors. The combined action of GABA and the benzodiazepine drug increases the frequency of chloride ion channel opening, resulting in hyperpolarization of the nerve membrane and reduced neuronal activity. In the reticular activating system, this depression produces sedation or hypnosis, depending upon the dose of drug administered.
Pharmacokinetics Benzodiazepines are lipid-soluble drugs that readily enter the CNS. They are well absorbed after oral administration. The benzodiazepines are metabolized by the drug microsomal enzymes. Some of the benzodiazepines are metabolized to active metabolites, which also produce sedation and hypnosis and prolong the duration of action. Unlike the barbiturates, the benzodiazepines do not cause enzyme induction of the microsomal metabolizing enzymes at therapeutic doses. Elimination is mainly by way of the urinary tract.
Flurazepam (Dalmane) Flurazepam is classified as a long-acting benzodiazepine. It forms several active metabolites, some of which have long half-lives. For this reason, the sedative and antianxiety effects of flurazepam are usually evident the day following a hypnotic dose. This prolonged action can be
Table 12:1
Frequently Prescribed Hypnotic Drugs Drug (Trade Name)
Duration
t 1/2 life (hours)
Comment
Eszopiclone (Lunesta)
Intermediate
6
Rapid onset
Zaleplon (Sonata)
Short
1
Rapid onset
Zolpidem (Ambien, Ambien-CR)
Short
1.5–4
Ambien-CR extends duration of action
Estazolam (ProSom)
Intermediate
10–24
No active metabolites
Flurazepam (Dalmane)
Long
45–100
Several active metabolites
Quazepam (Doral)
Long
39–100
Several active metabolites
Temazepam (Restoril )
Intermediate
10–40
No active metabolites
Triazolam (Halcion)
Short
1.5–3
Rapid onset
Benzodiazepines
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Note to the Health Care Professional Remind the patient to avoid hazardous activities when using hypnotic drugs. The depressant effects of the long-acting hypnotics can persist during the next day and can cause drowsiness and impaired motor coordination. Instruct the patient of the dangers of combining hypnotics with other CNS depressants such as alcohol and antianxiety drugs. The combination can cause significant CNS depression and respiratory difficulties.
useful in anxious patients when sedating drug effects are desired during the following day. On the other hand, daytime sedation and drowsiness may interfere with employment or other activities.
Temazepam (Restoril) Temazepam is an intermediate-acting hypnotic that does not form any important active metabolites. The duration of hypnotic action is 8 to 10 hours, and there are usually little or no drug effects evident the following day. One preparation of temazepam is marketed in a hard gelatin capsule that gives a delayed onset of action. This drug dosage form should be taken 1 to 2 hours before sleep is desired.
Triazolam (Halcion) Triazolam is a short-acting hypnotic with no active metabolites. This hypnotic does not usually cause residual effects the day following a hypnotic dose. However, the short duration of action may cause early morning awakenings.
Effects on Sleep Cycle All benzodiazepines produce similar effects on the sleep cycle. NREM stage 2 is increased while NREM stage 4 is usually decreased. The benzodiazepines do not significantly suppress REM sleep and therefore do not usually cause REM rebound when discontinued.
Advantages of Benzodiazepine Hypnotics over Barbiturates The benzodiazepines generally do not interfere with REM sleep. They produce less tolerance and therefore are effective for a few weeks longer than are the barbiturates when taken on a nightly basis. They also do not induce microsomal metabolizing enzymes significantly. When abused, the benzodiazepines generally cause less physical dependence than do barbiturates. These factors, 164
along with the low incidence of adverse effects, give the benzodiazepines a number of advantages over the barbiturates for both sedation and hypnosis.
Adverse Effects The benzodiazepine hypnotics are well tolerated and produce few adverse effects when used properly. Flurazepam, because of its longer half-life, may cause sedation or a “hangover effect” the following day. Triazolam, which has a very short duration of action, has been associated with rebound insomnia. This involves insomnia occurring over several days following abrupt discontinuance of the drug. In addition, triazolam has been associated with increased daytime anxiety. The adverse effects of the benzodiazepines are further discussed in Chapter 13.
Use of Flumazenil (Romazicon ) Flumazenil is a benzodiazepine receptor antagonist that may be administered intravenously to reverse the depressant effects of the benzodiazepine drugs. It can be used in the management of benzodiazepine overdose to antagonize the effects of excessive CNS and respiratory depression. Flumazenil has a half-life of approximately one hour and may require repeated administration. The sedative effects of eszopiclone, zaleplon, and zolpidem also are antagonized by flumazenil.
Cautions and Contraindications Pregnancy Benzodiazepine hypnotic drugs have been shown to cause harmful effects during pregnancy. They are designated as FDA Pregnancy Categories D and X and, therefore, should not be used during pregnancy.
Drug Interactions The benzodiazepines potentiate the actions of other CNS depressant drugs, such as alcohol and barbiturates. Such drugs should never be taken together unless specifically ordered by a physician. The metabolism of the benzodiazepines has been shown to be inhibited by cimetidine (Tagamet), a drug used in the treatment of intestinal ulcers. Cimetidine and other drugs that cause enzyme inhibition can increase the duration of action of the benzodiazepines. LO 12.5
M ISCELLANEOUS H YPNOTIC D RUGS The miscellaneous drugs are a diverse group of drugs with differing chemical structures and pharmacologic characteristics. These hypnotics include eszopiclone,
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zaleplon, and zolpidem. These drugs bind selectively to a subunit of the benzodiazepine receptor to increase the inhibitory effects of GABA. Because of this selectivity, these drugs lack other pharmacologic actions such as the anticonvulsant, muscle relaxing, and antianxiety effects produced by benzodiazepines and barbiturates. They also do not disrupt the normal stages of sleep like barbiturates and benzodiazepines. These drugs are summarized in Table 12:1. In addition, these drugs appear to be at low risk for the development of drug tolerance, dependency, and withdrawal reactions. Other miscellaneous drugs include ramelteon and chloral hydrate.
Eszopiclone (Lunesta) Eszopiclone is rapidly absorbed after oral administration, with a half-life of approximately 6 hours. Studies have demonstrated that eszopiclone sustained its ability to induce and maintain sleep when taken daily for 6 months. There is little evidence for the development of drug tolerance or dependency. However, abrupt cessation of drug following prolonged use may result in some withdrawal reactions. Common adverse effects include dizziness, headache, dry mouth, and mild impairment of memory.
Zaleplon (Sonata) Zaleplon is rapidly absorbed and provides a short duration of action. It is useful for individuals having difficulty falling asleep; it has not been shown to increase total sleep time. Adverse effects include dizziness, headache, and minor GI disturbances. The elderly may experience mental confusion and memory disturbances. The development of tolerance and dependency does not appear to be a significant problem and any withdrawal reactions are usually associated with abrupt cessation of drug following prolonged use.
Zolpidem (Ambien, Ambien-CR ) Zolpidem is currently the most widely prescribed hypnotic drug on the market. The drug is rapidly absorbed and has a rapid onset of action. Zolpidem decreases awakenings during the night and increases total sleep time. The extended release tablets supplied by AmbienCR (controlled release) further prolong the duration of action. As with eszopiclone and zaleplon, the development of drug tolerance, dependency, and withdrawal reactions are usually associated with abrupt cessation of drug following prolonged use. Common adverse effects include headache, dizziness, and nausea. The elderly may experience some confusion and memory disturbances.
Ramelteon (Rozerem) Ramelteon is classified as a melatonin agonist. Melatonin is produced by the pineal gland, released mainly at night, and involved with regulation of the sleep–wake cycle. The main effect of the drug is to promote sleep onset and it should be taken 30 minutes before bedtime. Adverse effects include headache, dizziness, and minor GI disturbances such as nausea and diarrhea. Ramelteon is not a controlled substance and is not associated with drug dependency.
Chloral Hydrate Chloral hydrate is an old drug and is related in a general way to alcohol. In the liver, it is metabolized by alcohol dehydrogenase to trichloroethanol, which also produces hypnotic effects (active metabolite). The main use of chloral hydrate is as a hypnotic, particularly in the elderly. The usual dosage is 500–1000 mg administered as capsules or syrup; rectal suppositories are also available. Chloral hydrate produces less suppression of REM sleep than do the barbiturates. Side effects usually involve excessive CNS depression and gastric irritation. Although capable of producing tolerance and addiction, chloral hydrate is not particularly popular with drug abusers.
Preferred Therapy for Insomnia and Sedation The preferred hypnotics for individuals having problems falling asleep and staying asleep are usually one of the miscellaneous drugs such as zolpidem (Ambien, AmbienCR) or eszopiclone (Lunesta). These drugs cause minimal drug tolerance and dependency. In addition, when taken nightly they are effective for longer periods of time than barbiturates or benzodiazepines. For individuals whose insomnia is complicated with anxiety or stressful situations, one of the benzodiazepines can be considered. Either temazepam (Restoril ) or estazolam (ProSom) provides an intermediate duration of action with little or no residual effects the following day. Flurazepam (Dalmane) or quazepam (Doral) may be considered when residual sedative and antianxiety actions are desired the following day. For individuals whose main problem is falling asleep, the shorter-acting drug zaleplon (Sonata) or the OTC drug ramelteon (Rozerem) may be helpful. The preferred drugs for sedation are usually one of the benzodiazepine drugs. There are a variety of choices depending on the duration of action that is desired. The sedative dosage varies depending on the desired degree of sedation but generally is one-third to one-half of the hypnotic dose. The drugs preferred for sedation are the Chapter 12 • Sedative-Hypnotic Drugs and Alcohol
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Patient Administration and Monitoring Monitor vital signs and patient response when barbiturates and benzodiazepines are administered parenterally.
Explain to patients the dangers of combining alcohol and other CNS depressant drugs with sedatives and hypnotics.
Explain the potential drug side effects: excessive drowsiness, mental confusion, and a drug hangover effect the following day.
Remind patients that these drugs should not be used for more than 2 weeks at a time unless otherwise instructed.
Explain to patients the dangers of activities such as driving while under the influence of sedative and hypnotic drugs.
benzodiazepines more commonly prescribed for their antianxiety effects (see Chapter 13). These drugs usually include diazepam (Valium), alprazolam (Xanax), and lorazepam (Ativan). LO 12.6
A LCOHOL Alcohol (ethanol, whiskey, ethyl alcohol, or grain alcohol) is probably the most widely used (self-prescribed) nonprescription sedative-hypnotic and antianxiety agent.
Pharmacological Effects Alcohol has many pharmacological effects that are seen throughout the body, including the CNS, heart, gastrointestinal tract, and kidneys.
CNS Effects The CNS is extremely sensitive to the depressant action of alcohol. As with other sedative-hypnotic drugs, alcohol produces a dose-dependent depression of the CNS. After drinking alcoholic beverages, people usually feel “stimulated,” uninhibited, and less self-conscious. However, this stimulation is actually due to an initial depression of inhibitory areas within the brain. As the level of alcohol in the brain increases, excitatory and inhibitory fibers are progressively depressed, leading to sedation, hypnosis, and possibly coma. Unlike the other sedativehypnotic drugs, alcohol produces some analgesia and antipyresis (reduces fever). The mechanisms of alcohol’s action in the CNS have not been fully established, but alcohol also appears to increase the inhibitory effects of GABA.
Vascular Effects In low to moderate amounts, alcohol does not produce any direct deleterious effects on the heart. However, alcohol may induce dilation of the blood vessels in the skin (cutaneous), producing a warm, flushed 166
Warn patients of the potential for drug dependency when barbiturate and benzodiazepine hypnotics are used continuously for prolonged periods.
sensation. The dilation of blood vessels may lead to a rapid loss of body heat, so that body temperature begins to fall. Depression of vasomotor centers in the CNS is most likely responsible for producing the peripheral vasodilation.
Gastrointestinal Effects Alcohol stimulates the secretion of saliva and gastric juices (acid and pepsin). Overall, this action usually results in an increased appetite. However, ingestion of strong concentrations of alcohol may irritate the gastric mucosa, causing a local inflammation (gastritis). Increased acid secretion coupled with gastritis may lead to gastrointestinal (GI) ulceration in sensitive patients.
Renal Effects Alcohol promotes an increased excretion of urine (diuresis), which is partly due to the increased fluid intake that accompanies the ingestion of alcoholic beverages. In addition, alcohol blocks the pituitary secretion of anti-diuretic hormone (ADH), which decreases the renal reabsorption of water. Therefore, the water is excreted into the urine. Alcohol inhibits the renal secretion of uric acid by an unknown mechanism that allows uric acid to build up in the blood. In susceptible patients (with gout or gouty arthritis), this elevation in uric acid levels may lead to attacks of joint inflammation.
Nutritional Effects Besides its direct effects on the various organs, alcohol exerts a profound influence on the nutritional state of individuals. Alcohol is a natural product that possesses calories. For this reason, many people often substitute alcohol for nutritionally rich foods, such as protein. Over a period of time, individuals who consume moderate to large amounts of alcohol in conjunction with a poorly balanced diet may suffer from vitamin and amino acid deficiencies. In particular, deficiency of the B vitamins leads to abnormal growth and function of nervous tissue.
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Therefore, multiple nutritional deficiencies associated with alcohol consumption produce various conditions such as neuropathies, dermatitis (pellagra), anemia, and psychosis.
neurological disorders such as Wernicke’s encephalopathy and Korsakoff’s psychosis. In addition, malnutrition and alcohol contribute to the production of fatty liver and cirrhosis of the liver.
Metabolism of Alcohol
Cautions and Contraindications
Alcohol is readily absorbed throughout the entire GI tract following ingestion. Subsequently, alcohol is distributed to all tissues. However, the CNS receives a significant concentration of alcohol because of its rich blood supply. The concentration of alcohol in the brain is proportional to the concentration of alcohol in the blood. Unlike other drugs, alcohol is metabolized at a constant rate in the liver. No matter how much alcohol is consumed, only 10 to 15 ml of pure alcohol per hour is metabolized, which is the amount of alcohol in one beer, a glass of wine, or an average-size cocktail. This limits the amount of alcohol that can be consumed without producing intoxication. Alcohol is metabolized primarily to acetaldehyde, which the body can use in the synthesis of cholesterol and fatty acids. Overall, alcohol is efficiently metabolized (about 95 percent) to useful biochemical products and water. Enzyme induction develops during chronic use of alcohol. Therefore, habitual drinkers often experience shorter durations of action of other drugs metabolized by the microsomal system of the liver (oral anticoagulants and many others).
The symptoms of alcohol intoxication often resemble those associated with diabetic coma, head injuries, and drug overdose (other sedative-hypnotics). Patients who appear intoxicated should always be kept for observation until an accurate diagnosis is made. If possible, the blood alcohol level should be determined to confirm the suspected diagnosis. Alcohol should never be combined with other CNS depressant medications. Potentiation occurs with any central-acting depressants, including muscle relaxants, anesthetics, analgesics, and antianxiety drugs. Alcohol is absolutely contraindicated in patients who have hepatic or renal disease, ulcers, hyperacidity, or epilepsy.
Adverse Effects The adverse effects associated with the use of alcohol are separated into acute and chronic effects. Acute intoxication (inebriation) produces extensive CNS depression. Individuals may exhibit ataxia, impaired speech, blurred vision, and loss of memory, similar to the symptoms of intoxication caused by other sedative-hypnotic drugs. When CNS depression is severe, stupor and coma may result. The skin is cold and clammy, the body temperature falls, and the heart rate may increase. Treatment is usually directed at supporting respiration, so that the brain remains well oxygenated. Chronic consumption of alcohol is associated with progressive changes in cell function. Elevated blood alcohol levels for long periods result ultimately in drug tolerance and physical dependence. The abstinence syndrome associated with alcohol addiction is similar to that described for the barbiturates and benzodiazepines. In addition, chronic use of alcohol produces alterations in body metabolism, some of which may be due to the development of malnutrition. Alcohol-induced malnutrition and vitamin deficiency can cause a number of
Pregnancy The consumption of alcohol has been associated with harmful fetal effects and should be avoided during pregnancy. Alcohol readily crosses the placenta and distributes to all tissues of the fetus. Infants who were exposed to circulating levels of alcohol in utero have shown depressed respiration and reflexes at birth. Babies born to alcoholic mothers are unusually small, are frequently premature, and may be mentally retarded. It is not unusual for a newborn of an alcoholic mother to undergo withdrawal symptoms after birth. Fetal alcohol syndrome is the term used to describe the fetal abnormalities that may include low IQ, microcephaly, and a variety of facial abnormalities.
Clinical Indications When applied to the skin, alcohol produces a cooling effect, due to rapid evaporation from the skin surface. For this reason, it is used as a sponge bath to reduce elevated body temperature. Also, 70 percent alcohol applied to the skin acts as a bactericidal agent (disinfectant). There is very little medicinal value associated with the consumption of alcohol. However, many overthe-counter (nonprescription) cold remedies and cough syrups contain a significant amount of alcohol; the alcohol present in these preparations is sufficient to produce sedation and hypnosis. Therefore, exposure of patients to alcohol may occur without their knowledge.
Disulfiram (Antabuse) Disulfiram is a drug used to treat chronic alcoholism. It interferes with the metabolism of alcohol. Alcohol Chapter 12 • Sedative-Hypnotic Drugs and Alcohol
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is metabolized through a series of steps to acetaldehyde, which is then converted into acetyl coenzyme A (CoA). alcohol ↓ acetaldehyde ↓ acetyl coenzyme A
Disulfiram slows the conversion of acetaldehyde to acetyl coenzyme A. Therefore, acetaldehyde accumulates
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in the blood, producing nausea, vomiting, headache, and hypotension. This is known as a disulfiram reaction. Patients taking disulfiram are instructed not to ingest any alcoholic beverages, including cough syrups, special wine sauces, and fermented beverages (cider). As long as a patient is taking disulfiram, even a small amount of alcohol (1 ounce) will produce the unpleasant effects. In this manner, the disulfiram therapy acts as a reinforcing deterrent to alcohol consumption as long as the individual is willing to take the drug.
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Chapter Review Understanding Terminology Answer the following questions. 1. Differentiate between REM sleep and NREM sleep. (LO 12.1) 2. What is the difference between a sedative and a hypnotic? (LO 12.3) 3. Explain the meaning of automatism. (LO 12.3) 4. Differentiate between barbiturates and nonbarbiturates. (LO 12.5) 5. What is GABA an abbreviation for? (LO 12.2)
Acquiring Knowledge Answer the following questions. 1. What is the major indication for the use of sedatives and hypnotics? (LO 12.1) 2. Explain the mechanism of action of benzodiazepine hypnotics. What is the main site of action to produce this effect? (LO 12.4) 3. List the different stages of sleep and the characteristics of each. (LO 12.1) 4. How do barbiturates alter the normal sleep cycle? (LO 12.3) 5. What is the importance of enzyme induction caused by barbiturate drugs? (LO 12.3) 6. What adverse effects are caused by barbiturates? (LO 12.3) 7. How does GABA normally function? (LO 12.2) 8. Explain the mechanism of action of zolpidem and zaleplon. (LO 12.5) 9. How do benzodiazepine hypnotics alter the sleep cycle? (LO 12.4) 10. What is the main difference between flurazepam (Dalmane) and triazolam (Halcion)? (LO 12.4) 11. What are the advantages of the benzodiazepines over the barbiturate hypnotics? (LO 12.3, 12.4) 12. List some of the effects that alcohol produces on the different body systems. (LO 12.6) 13. Explain how disulfiram (Antabuse) is used in the treatment of alcoholism and describe the disulfiram reaction. (LO 12.6)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. An 82-year-old woman has been taking a sleeping pill for the past 6 months to help her fall asleep. What can you tell her about the use of hypnotic drugs? (LO 12.3) 2. Mary’s husband John occasionally takes Dalmane when he has trouble sleeping. He came home late last night after a banquet and a few too many drinks; he took a Dalmane capsule because he wasn’t tired and he had to get up early for an important meeting. At 8 a.m., John was sound asleep and Mary couldn’t seem to wake him up. What do you think may have happened? (LO 12.4) 3. You receive a phone call at the doctor’s office from Mr. Smith, who has a prescription for Antabuse. He complains that he feels terrible and has been vomiting. He claims to have just developed a chest cold and has taken a spoonful of Vicks cough syrup. Mr. Smith doesn’t think the vomiting has anything to do with the cold. What do you think? (LO 12.6) 4. A young man with a history of occasional drug abuse is in the doctor’s office complaining of difficulty sleeping. The physician is writing a prescription for a hypnotic with no refills. Which hypnotic agent might be the best choice for this patient? (LO 12.5)
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Chapter Review Continued Use the appropriate reference books if needed for the following questions. 5. June is a 36-year-old alcoholic. She has unsuccessfully attempted to quit drinking multiple times. Her physician has decided to initiate disulfiram therapy. What should June be told before taking this medication? (LO 12.6) 6. John is a healthy 29-year-old who has recently had trouble sleeping. His physician has prescribed Dalmane 30 mg. While talking with John, he tells you how happy he is to know that he is going to get a good night’s sleep. He works in a high-energy office and was concerned that he might be in danger of losing his job due to his recent lack of energy. Do you think this should be brought to the physician’s attention? Why? Would you expect the drug therapy to change? If so, which medication do you think it might be changed to? (LO 12.4) 7. Julie has never had trouble sleeping until the past month. She is going through a stressful period and is having difficulty falling asleep. Once asleep, she usually sleeps through the night. Her care provider had prescribed Ambien 5 mg in a quantity to last 2 weeks. Do you feel this is appropriate? Why? (LO 12.5)
Multiple Choice Use your critical-thinking skills to answer the following questions. 1. Barbiturate and benzodiazepine hypnotics both (LO 12.3, 12.4) A. increase NREM stage 2 sleep B. decrease REM sleep C. decrease NREM stage 4 sleep D. only A and C are true 2. Disadvantages to the use of barbiturate hypnotics include (LO 12.3) A. development of drug tolerance B. risk of drug dependency C. disruption of normal stages of sleep D. all statements are true 3. The correct statement concerning the use of hypnotic drugs is (LO 12.3, 12.4, 12.5) A. zolpidem binds to the GABA receptor B. benzodiazepines increase chloride channel opening C. barbiturates block the GABA receptor D. ramelteon is a melatonin antagonist 4. Flurazepam (LO 12.4) A. is classified as long-acting B. forms active metabolites C. may cause next-day residual effects D. all statements are true 5. Triazolam (LO 12.4) A. forms active metabolites B. may cause next-day residual effects C. may cause early morning awakenings D. is classified as long-acting 6. Eszopiclone (LO 12.5) A. is classified as a benzodiazepine B. has a half-life of 1–2 hours C. increases total sleep time D. is used as an antianxiety agent 7. Zolpidem (LO 12.5) A. binds to the benzodiazepine-1 (BZD1) receptor B. is useful as a muscle relaxant C. has a slow onset of action D. is useful as an anticonvulsant
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Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Which stages of the sleep cycle are important for restoration? (LO 12.1) A. stage 1 NREM B. stage 2 NREM C. stages 3 and 4 NREM D. REM 2. Barbiturate sedatives work by (LO 12.2) A. binding to GABA receptors B. increasing the influx of chloride C. depolarizing nerves D. decreasing the activity of RAS 3. Select all of the adverse effects of barbiturates. (LO 12.3) A. slurred speech B. ataxia C. irritability D. automatism 4. The differences between long-acting and short-acting benzodiazepines include (LO 12.4) A. the shorter the duration of action, the more active the metabolites B. the shorter the duration of action, the more drug effect the next day C. the longer the duration of action, the more active the metabolites D. the longer the duration of action, the less daytime sedation 5. Alcohol has pharmacological effects on which body systems? (LO 12.6) A. central nervous system B. gastrointestinal system C. renal system D. vascular system
Sequencing Place the following in order of longest half-life to shortest half-life. (LO 12.4) _______________
_______________
_______________
Last
_______________ First
Halcion Restoril ProSom Dalmane
Classification Place each drug under the appropriate use. (LO 12.3, 12.4, 12.5) ProSom
Lunesta
Restoril
Xanax
Rozerem
Ambien
Valium
Sonata
Falling & staying asleep
Insomnia due to stress
Falling asleep
Sedation
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Chapter Review Continued Matching Match the following effects with the appropriate class of drugs. (LO 12.2, 12.4, 12.5) a. barbiturates b. benzodiazepines c. ramelteon d. zolpidem e. zaleplon 1. _____ melatonin antagonist 2. _____ used primarily for those who have difficulty falling asleep 3. _____ referred to as antianxiety drugs 4. _____ increases stage 2 NREM 5. _____ decreases awakening during the night
Labeling Fill in the missing labels. (LO 12.1)
Stress ploym Marr iage ent
Unem
s
am Ex
Old a
ge
Bills Work
Effects of drug: Gradual depresslon of CNS
For interactive animations, videos, and assessment, visit:
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Chapter 13
A ntipsychotic and A ntianxiety D rugs DRUG CLASS AT A GLANCE OTC
NO
PRESCRIPTION YES SCHEDULED DRUGS
YES, benzodiazepines
FDA PREGNANCY CATEGORY
B, C, D (benzodiazepines)
INDICATIONS Schizophrenia, psychoses, anxiety
KEY TERMS akathisia: continuous body movement in which an individual is restless or constantly paces about. antianxiety drug: drug used to treat anxiety; these drugs are also referred to as anxiolytics. antipsychotic drug: drug used to treat schizophrenia and other psychotic conditions. anxiety: a state of anxiousness and hyperemotionalism that occurs with uncertainty, stress, and fearful situations. dystonic reaction: reaction characterized by muscle spasms, twitching, facial grimacing, or torticollis. extrapyramidal syndrome (EPS): movement disorders such as akathisia, dystonia, and parkinsonism caused by antipsychotic drug therapy. neuroleptic malignant syndrome (NMS): toxic syndrome associated with the use of antipsychotic drugs. parkinsonism: disease or drug-induced condition characterized by muscular rigidity, tremors, and disturbances of movement. psychosis: form of mental illness that produces bizarre behavior and deterioration of the personality. schizophrenia: major form of psychosis; behavior is inappropriate. tardive dyskinesia: drug-induced involuntary movements of the lips, jaw, tongue, and extremities.
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Learning Outcomes
After studying this chapter, you should be able to
13.4 describe the actions and adverse effects of the thioxanthine antipsychotic drugs.
13.1 explain the importance of dopamine and serotonin in relationship to psychosis and antipsychotic drug therapy.
13.5 explain the actions and advantages of the atypical antipsychotic drugs when compared to the typical antipsychotic drugs.
13.2 list the different pharmacologic actions of the phenothiazine drugs and describe the adverse neurological effects associated with these drugs.
13.6 compare the mechanism of action and pharmacologic effects of the antianxiety benzodiazepines with buspirone.
13.3 compare the pharmacologic actions and adverse effects of the butyrophenones with the phenothiazines.
Introduction
The term mental illness refers to a number of emotional and mental disturbances that involve abnormal changes in personality and behavior. These changes may affect the ability of individuals to communicate with other people or to function in normal activities. Psychosis is a mental condition characterized by disturbed thought processes, delusions, and hallucinations. While psychotic behavior can be caused by a variety of conditions, one of the main causes is schizophrenia. Symptoms of schizophrenia include bizarre behavior, auditory and visual hallucinations, lack of motivation and emotional expression, and diminished speech and thought processes. The cause of schizophrenia involves genetic defects that cause abnormal neural development. Excessive activity of certain brain neurotransmitters, especially dopamine and serotonin, in the cerebral cortex and limbic system appear to be responsible for the psychotic behavior. Drugs referred to as antipsychotics are used to treat these conditions Anxiety is a very common emotion and increases whenever there is uncertainty or fear about some event or life circumstance. Certain types of anxiety have been classified and include general anxiety disorder (GAD), panic disorder, obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD). The limbic system plays a major role in the regulation and control of emotions. In stressful and uncertain situations, the activity of the limbic system dramatically increases. Anxiety also activates the sympathetic nervous system and the reticular activating system, which in turn cause hyperarousal of the cerebral cortex. The result is a highly emotional state accompanied by many physical symptoms that can interfere with normal function and daily activities. Drugs used to treat anxiety, the benzodiazepines and buspirone, are referred to as the antianxiety drugs or anxiolytics. In addition, some of the antidepressant drugs (Chapter 14) are also effective for the treatment of anxiety.
LO 1 13. 13.1 3.1 1
LO 1 13.2 13. 3.2 2
LO 13.3 3
LO 13.4 4
LO 13.5
A NTIPSYCHOTIC D RUGS Antipsychotic drugs are used to suppress the symptoms of schizophrenia and other psychotic conditions. The main site of action of antipsychotic drugs is on neural pathways involving the cerebral cortex and limbic system. The cause of psychosis is not completely understood. However, excessive activity of neurotransmitters in the 174
cortical and limbic pathways is involved in the development of schizophrenia and other psychoses. Dopamine (DA) appears to be particularly important, and drugs that block or reduce the effects of dopamine are effective in treating psychosis, especially schizophrenia. There are at least five different types of DA receptors, identified as D1 through D5. However, the mechanism of action of antipsychotic drugs involves the ability of these drugs
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to block a specific DA receptor, the D2 receptor. This reduces dopaminergic activity by preventing dopamine from binding to and activating its receptors. Excessive blockade of dopamine receptors is the main cause of the extrapyramidal syndrome (EPS). Serotonin (5HT) is another brain neurotransmitter that is involved in psychotic behavior. There are a number of different 5HT receptors but the receptor identified as 5HT2A is the one most important for antipsychotic effects. Antipsychotic drugs primarily antagonize both D2 and 5HT2A receptors. The main difference among the various antipsychotic drug classes is the degree to which they block each of these two neurotransmitter receptors. Antipsychotic drugs also affect other neurotransmitter receptors, but these actions are associated with adverse effects. There are four classes of antipsychotic drugs. The phenothiazine, butyrophenone, and thioxanthine drugs are referred to as “typical” because they all primarily block D2 receptors. They also produce a higher incidence of EPS because of the D2 blockade. The remaining drug class is referred to as the “atypical” antipsychotic drugs. Unlike the other three antipsychotic drug classes, the atypical drugs reduce serotonin activity more than they reduce the activity of dopamine, and for that reason they cause a significantly lower incidence of EPS. Several classes of drugs are used for their antipsychotic effects. In addition to blocking dopamine and serotonin, most antipsychotic drugs produce varying degrees of anticholinergic, alpha-adrenergic-blocking, and antihistaminic effects. Figure 13.1 provides an overview of the neurotransmitter receptors blocked by antipsychotic drugs and the resulting drug effects.
Phenothiazines The term phenothiazine refers to the basic chemical structure of a large number of drugs similar in structure and pharmacological action. Although some of these drugs are more effective than others, all produce the same pharmacological effects. These drugs block D2 receptors to a greater degree than they block 5HT2A receptors. The first phenothiazine, chlorpromazine, was discovered in the early 1950s. Within a few years, chlorpromazine had revolutionized the treatment of mental illness. Many patients who were previously institutionalized were able to return home and assume more active roles in society. Within a few years, the number of patients in mental institutions was cut almost in half. The phenothiazines are a very active group of drugs. In addition to an antipsychotic effect, they possess anticholinergic, antihistaminic, alpha-adrenergic-blocking,
and antiemetic effects. These additional effects allow the phenothiazines to be used for treating nausea, vomiting, pruritus, and certain allergic reactions; however, these actions also increase adverse drug reactions. The phenothiazines are administered orally (PO) and parenterally (IM and IV). Table 13:1 lists the most frequently used phenothiazines and their main pharmacologic features.
Antipsychotic Effects The main effects of the antipsychotic drugs are to reduce the bizarre behavior, hallucinations, and irrational thought disorders of psychosis without significantly depressing other intellectual functions. The antipsychotic effects usually require several weeks to fully develop. With drug therapy, patients usually demonstrate decreased interest in the surroundings and less behavioral activation. However, routine daily activities can be carried out, and patients are able to communicate more rationally. Although the psychosis is not cured, it is possible to control it adequately with the proper medication. In addition, patients are usually more amenable to psychotherapy and other treatment measures.
Adverse Effects Common adverse effects, such as dry mouth, constipation, visual disturbances, and sedation, are due to anticholinergic and antihistaminic actions. Alpha-blocking actions may reduce blood pressure and cause postural hypotension. Because antipsychotic drugs block the effects of dopamine, a number of neurological side effects involving the basal ganglia can occur. Dopamine functions as a neurotransmitter in the basal ganglia of the brain. The basal ganglia are important in the regulation of skeletal muscle tone and movement (see Chapter 17). In addition, blockade of dopamine receptors also may increase prolactin levels, which can cause menstrual irregularities in women and gynecomastia in males. Blockade of DA receptors in the basal ganglia may cause a number of movement disorders. These disorders are usually referred to as the extrapyramidal syndrome (EPS). Dystonic reactions are characterized by muscle spasms, twitching, facial grimacing, and torticollis (wryneck). Akathisia refers to continuous body movement in which the individual is restless or constantly paces about. Parkinsonism involves development of muscular rigidity, tremors, and other disturbances of movement. Reducing the dosage, stopping the drug, or administering centrally acting anticholinergic drugs usually improves these three neurological conditions. Tardive dyskinesia is a more serious condition that may develop after long-term antipsychotic therapy. This condition involves involuntary movements of the Chapter 13 • Antipsychotic and Antianxiety Drugs
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Figure 13.1 Nerve ending
Neurotransmitters and Receptor Sites Blocked by Antipsychotic Drugs High-potency blocking drugs
Receptors
Drug effect
Antipsychotic effect (higher incidence of EPS) DA
Fluphenazine Haloperidol Thiothixene D2
(a) Dopaminergic Antipsychotic effect (lower incidence of EPS) 5HT
Aripiprazole Olanzapine Risperidone 5HT2A
(b) Serotonergic
Anticholinergic effects ACH
Chlorpromazine Thioridazine Clozapine Cholinergic
(c) Cholinergic
Postural hypotension NE
Chlorpromazine Thioridazine Clozapine ␣-Adrenergic
(d) Adrenergic
Sedation antihistaminic H
Chlorpromazine Thioridazine Clozapine Histamine-1
(e) Histaminergic (a) Phenothiazine, butyrophenone, and thioxanthene drugs primarily block D 2 receptors to produce the antipsychotic effect, and also significant EPS. (b) Atypical antipsychotics primarily block 5HT 2A receptors to produce antipsychotic effects and less EPS. (c) Antipsychotic drugs with prominent anticholinergic effects. (d) Antipsychotic drugs with increased alpha-adrenergic-blocking actions that cause postural hypotension. (e) Antipsychotic drugs with antihistaminic actions and that promote sedation.
lips, jaw, tongue, and extremities. The symptoms of tardive dyskinesia often appear when antipsychotic drug treatment is stopped. The symptoms can be suppressed by reinstituting the drug or by increasing the dose of the antipsychotic drug. However, the condition of tardive dyskinesia continues to progress and will be worse when the drug is stopped. 176
A serious and potentially fatal condition, neuroleptic malignant syndrome (NMS), is also associated with the use of antipsychotic drugs. This syndrome is characterized by hyperthermia, muscular rigidity, catatonia (patient appears frozen in position), and autonomic nervous system instability. Treatment is immediately required and involves stopping antipsychotic
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Table 13:1
Representative Antipsychotic Drugs and Their Main Pharmacologic Features Drug (Trade Name)
Potency
Sedation
EPS
AC
PH
Chlorpromazine (Thorazine)
Low
High
Medium
High
High
Fluphenazine (Prolixin)
High
Low
High
Medium
Low
Thioridazine (Mellaril)
Low
High
Medium
High
High
Trifluoperazine (Stelazine)
High
Medium
High
Medium
Low
High
Low
High
Low
Low
High
Medium
High
Medium
Low
Aripiprazole (Abilify)
High
Low
Low
Low
Low
Clozapine (Clozaril)
Medium
Medium
Low
High
High
Iloperidone (Fanapt)
Medium
Low
Low
Low
Medium
Olanzapine (Zyprexa)
High
Medium
Low
Low
Low
Quetiapine (Seroquel)
Low
Medium
Low
Medium
Medium
Risperidone (Risperdal)
High
Low
Low
Low
Medium
Asenapine (Saphris)
Medium
Medium
Low
Low
Medium
Ziprasidone (Geodon)
Medium
Low
Low
Low
Low
Phenothiazines
Butyrophenones Haloperidol (Haldol) Thioxanthenes Thiothixene (Navane) Atypical antipsychotics
EPS – extrapyramidal syndrome, AC – anticholinergic effects, PH – postural hypotension
drug administration and symptomatic treatment of the symptoms. Drug allergy is an infrequent but potentially dangerous complication of phenothiazine therapy. Allergic symptoms usually involve skin rashes and photosensitivity, blood disorders, and liver toxicity (cholestatic jaundice). Other miscellaneous adverse effects include skin pigmentation, ocular deposits (lens and cornea), and various endocrine disturbances.
Butyrophenones The butyrophenones are high-potency drugs that differ chemically from the phenothiazines but that produce the same type of antipsychotic effects. The main drug of this group is haloperidol (Haldol).
Actions and Clinical Uses On a milligram basis, the butyrophenones are more potent than the phenothiazines. Like the phenothiazines, Chapter 13 • Antipsychotic and Antianxiety Drugs
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the butyrophenones block D2 receptors more than 5HT2A receptors. The butyrophenones produce a lower incidence of peripheral effects (alpha-adrenergic blockade, anticholinergic, and antihistaminic), but greater movement disturbances. Haloperidol is especially useful in the treatment of highly agitated and manic patients. In addition, haloperidol is indicated to suppress the motor tics and vocalizations that characterize Gilles de la Tourette’s syndrome.
Adverse Effects The adverse effects of the butyrophenones are similar to those of the phenothiazines. However, the butyrophenones, haloperidol in particular, produce the highest incidence of extrapyramidal symptoms (EPS). There is also the potential for development of tardive dyskinesia and neuroleptic malignant syndrome.
Thioxanthenes Thioxanthenes have chemical structures very similar to those of phenothiazines. Like phenothiazines and butyrophenones, thioxanthenes exert antipsychotic effects by blocking D2 receptors more than 5HT2A receptors. The most important thioxanthene is thiothixene (Navane).
Actions The pharmacologic actions of thiothixene are similar to those of the phenothiazines. Thiothixene is a highpotency drug that is associated with higher incidences of EPS. Thiothixene generally causes less sedation and fewer anticholinergic and alpha-blocking effects than those of chlorpromazine.
Adverse Effects The most frequent adverse effects of the thioxanthenes include drowsiness and postural hypotension. Patients who become allergic to these drugs may develop dermatitis, obstructive jaundice, or blood disorders (anemia and leukopenia). Like other antipsychotic drugs, the thioxanthenes may cause parkinsonian symptoms and other extrapyramidal disturbances of movement.
Atypical Antipsychotic Drugs Unlike the phenothiazine, butyrophenone, and thioxanthene drugs, the atypical antipsychotic drugs affect and reduce the activity of 5HT2A receptors more than they interfere with D2 receptors. Because they have less effect on D2 receptors, they are associated with a lower incidence of EPS, which is the main reason they are considered atypical. However, as with all antipsychotic drugs there is the potential for development of EPS, tardive dyskinesia, and neuroleptic malignant syndrome. Atypical drugs are associated with several metabolic 178
disturbances such as weight gain, elevated triglycerides (hyperlipidemia), and development of diabetes mellitus. The atypical drugs and their main pharmacologic features are summarized in Table 13:1.
Aripiprazole (Abilify) Aripiprazole is one of the newer atypical drugs that affects a number of DA and 5HT receptors. The main action of aripiprazole is antagonism of both D2 and 5HT2A receptors. Aripiprazole is a high-potency drug that is associated with low incidences of sedation, EPS, and autonomic and metabolic disturbances. Common side effects include dizziness, headache, constipation, anxiety, and sleep disturbances. Aripiprazole may decrease sweating and cause increased body temperature and fever, especially during physical exertion.
Clozapine (Clozaril ) Clozapine provides moderate antipsychotic potency along with a low incidence of EPS. However, the use of clozapine is associated with higher incidences of sedation, seizures, weight gain, and agranulocytosis. The latter effect involves a decrease in white blood cells (WBCs), which may increase infections and requires periodic WBC monitoring. Anticholinergic effects and postural hypotension also are prominent. Because of the higher incidence of adverse effects, other atypical drugs are usually preferred.
Risperidone (Risperdal ) Risperidone is a high-potency drug that antagonizes 5HT2A more than D2 receptors. The drug is mildly sedating and produces a low incidence of EPS, although the incidence of sedation and EPS increases at higher doses. Postural hypotension and some weight gain also may occur. The drug is also available for IM injection (Risperdal Consta).
Olanzapine (Zyprexa) Olanzapine is a high-potency drug associated with a low incidence of EPS. In addition to regular tablets, there is a tablet formulation of Zyprexa (Zyprexa Zydis) that rapidly dissolves in the mouth and an injectable preparation for IM administration. Adverse effects include dizziness, sedation, weight gain, and postural hypotension. Olanzapine also has shown effectiveness in the treatment of acute mania and bipolar disorder.
Cautions and Contraindications Pregnancy Most antipsychotic drugs are designated either Food and Drug Administration (FDA) Pregnancy Category B or C; a few of the drugs have not been rated. As always, the use of drugs during pregnancy should be avoided if at all possible and used only when the benefits outweigh the risks.
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Drug Interactions As previously discussed, many of the antipsychotic drugs produce anticholinergic, alpha-blocking, antihistaminic, and central nervous system (CNS) depressing effects. Therefore, these drugs will interact with all other drugs that also produce these pharmacologic effects. Anticholinergic drugs (atropine-like) decrease the activity of the urinary and intestinal tracts and increase cardiac activity. They also tend to cause CNS depression and mental disturbances, especially in the elderly. Remember also that anticholinergic drugs are contraindicated or used with caution in individuals with glaucoma, prostate hypertrophy, and urinary and intestinal obstruction (see Chapter 7). Many antihistamine drugs possess anticholinergic activity and also cause sedation. Consequently, other anticholinergic drugs taken together with antipsychotic drugs will increase the frequency and severity of anticholinergic adverse reactions. Alpha-blocking activity (blocks alpha effects of norepinephrine and epinephrine) produces a lowering of blood pressure. Individuals taking alpha-blockers for hypertension, or taking other antihypertensive medication, may experience hypotension, orthostatic hypotension, fainting, and the other adverse effects of alpha blockade (see Chapter 6). The CNS depressant effects of antipsychotic drugs will be increased by all other drugs that also cause sedation, hypnosis, and depression. These include alcohol, barbiturates, benzodiazepines, antihistamines, tricyclic antidepressants, anticholinergics, and narcotics. When taken together these drugs may cause excessive CNS depression leading to coma, respiratory depression or arrest, and death.
Preferred Therapy for Schizophrenia and Psychosis Due to the complex nature of schizophrenia and the different degrees of psychotic behavior, it is difficult to select one or two drugs as the drugs of choice. However, with regard to antipsychotic drug classes, the atypical drugs are now the preferred therapy. The advantages of these drugs include lower incidences of EPS, sedation, and other neurologic disturbances. In addition, with the exception of clozapine, the atypical drugs do not cause significant anticholinergic, alpha-adrenergic-blocking, or antihistaminic actions compared to some of the other drugs. The other antipsychotics usually serve as alternatives to the atypical drugs when patient conditions or contraindications exist. Often there is a trial period where different drugs are tried in order to find the most suitable drug for a particular patient.
Patient Administration and Monitoring Monitor vital signs and patient response frequently when these drugs are administered parenterally, especially blood pressure and heart activity. Explain to patient the common side effects: dry mouth, sedation, sleepiness, dizziness, blurred vision. Instruct patient to report tremors, muscular rigidity, fever, disturbances of movement, visual disturbances, excessive weakness or feelings of faintness, and difficulties with urination and defecation. Inform patients not to take other medications unless they check with their physician or pharmacist; there are many drug interactions with antipsychotic drugs.
LO 13.6
A NTIANXIETY D RUGS Anxiety, tension, and nervousness are effects caused by uncertainty and various situations that are interpreted as being threatening or potentially dangerous. The perceived dangers may be real or due to personal insecurities or unconscious psychological conflicts. Physiologic and behavioral changes—trembling, sweating, nausea, loss of appetite, rapid heartbeat, and emotionalism—are caused by activation of the limbic and sympathetic nervous systems. The limbic system is a group of brain areas (amygdala, hippocampus, hypothalamus, lower parts of the cerebral cortex, others) that are interconnected by a neural pathway. The limbic system is involved with emotional and behavioral responses associated with reward, punishment, anger, fear, and anxiety. An important inhibitory neurotransmitter that functions to keep our emotions and behavior under control is gammaaminobutyric acid, GABA (see Chapter 12). When an anxiety condition is prolonged, there are significant behavioral and emotional changes. Antianxiety drugs, also referred to as anxiolytics, are used to calm individuals and reduce the unpleasant aspects of anxiety and hyperemotionalism. In addition, the benzodiazepine antianxiety drugs also are used as sedatives, hypnotics, anticonvulsants, and skeletal muscle relaxants (see Chapters 9, 12, and 16).
Benzodiazepines The most important antianxiety drugs belong to a chemical class known as the benzodiazepines. Diazepam (Valium) and chlordiazepoxide (Librium) were the first Chapter 13 • Antipsychotic and Antianxiety Drugs
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benzodiazepines introduced and have been available for almost 50 years. A number of the benzodiazepines are marketed as hypnotics and were discussed in Chapter 12. Additional benzodiazepine drugs are listed in Table 13:2.
Mechanism of Action The benzodiazepines decrease the excitability and the functional activity of specific areas of the brain and spinal cord. As previously discussed in Chapter 12, gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the CNS that, when released from nerve endings, binds to receptors (called GABA receptors) located on the membranes of other neurons. GABA appears to allow more chloride ions (Cl –) to pass into the neurons, which makes the inside of the neuron more negatively charged (hyperpolarization). Hyperpolarization of the neuron reduces neuronal excitability and consequently produces a depressant effect on those neurons. The benzodiazepine drugs bind to neuronal membranes at receptor sites (referred to as the benzodiazepine receptors) that are actually a part of the GABA receptors. When both GABA and a benzodiazepine drug
are bound to their receptors, more chloride ions pass into the neuron than when only GABA is bound alone (Figure 13.2). Consequently, a greater degree of hyperpolarization and neuronal depression is produced. Simply stated, benzodiazepines are believed to increase the inhibitory actions of GABA, which results in reduced activity (depression) of specific areas of the CNS.
Sites of Action There are four main areas of the CNS where the benzodiazepines exert their inhibitory effects: the limbic system, reticular formation, cerebral cortex, and spinal cord. The limbic system is involved with regulation of emotional and behavioral responses. Any emotional or anxiety-producing situation increases the activity of the limbic system. GABA normally functions to inhibit excess stimulation of the limbic system. When anxiety becomes excessive and contributes to neurotic behavior, benzodiazepines are prescribed to decrease the activity of the limbic system. Anxious individuals usually calm down, are less emotional, and are in a better mental state
Table 13:2
Benzodiazepine Drugs Drug (Trade Name)
Main use
Usual dose (mg/day)
Chlordiazepoxide (Librium)
Antianxiety, alcohol withdrawal
10–100
Clonazepam (Klonopin)
Antianxiety, anticonvulsant
0.5–12
Clorazepate (Tranxene)
Antianxiety, alcohol withdrawal
15–60
Diazepam (Valium)
Antianxiety, pre-op medication, alcohol withdrawal, anticonvulsant, muscle relaxer
2–40
Flurazepam (Dalmane)
Hypnotic
15–30 mg at bedtime
Alprazolam (Xanax)
Antianxiety, panic disorder, sedation
0.5–10
Lorazepam (Ativan)
Antianxiety, sedation, anticonvulsant
2–6
Oxazepam (Serax)
Antianxiety, sedation
30–120
Temazepam (Restoril)
Hypnotic
15–30 mg at bedtime
Triazolam (Halcion)
Hypnotic
0.25–0.5 mg at bedtime
Long acting
Short acting
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Figure 13.2 Diagrammatic Representation of the Chloride Channel Extracellular Cl⫺
GABA 
GABA 
␣
␥
␣
Benzodiazepines Flumazenil
GABA has an important function in the spinal cord. It helps regulate the degree of skeletal muscle tone and the responsiveness of spinal reflexes that also maintain skeletal muscle activity. By increasing the inhibitory actions of GABA, benzodiazepines decrease skeletal muscle tone. Relaxation of skeletal muscle is helpful in treating back injuries, spinal cord injuries, muscular dystrophy, and cerebral palsy, where muscle spasticity is usually present. Relaxation of skeletal muscle also is believed to contribute to the antianxiety effect, since increased muscle tension is a common finding in anxious individuals.
Pharmacokinetics
Ion channel Intracellular
This diagram shows the location of the receptor sites for gamma-aminobutyric acid (GABA) and for the benzodiazepine drugs used to treat anxiety. Both GABA and the benzodiazepine drugs increase the influx of chloride ions that makes the inside of the neuron more negative (hyperpolarization) and inhibits neuronal activity in the limbic system. Flumazenil is a benzodiazepine receptor antagonist used to reverse the effects of the benzodiazepine drugs.
to deal with the situations that cause the anxiety. This is referred to as the antianxiety effect. The reticular formation regulates the degree of wakefulness and alertness. Amphetamines and other CNS stimulants increase the activity of the reticular formation, which causes increased wakefulness and hyperactivity. GABA normally functions to decrease the activity of the reticular formation. Benzodiazepines, which increase the inhibitory actions of GABA, are used to produce sedation and hypnosis (sleep). A few of the benzodiazepines, those previously discussed in Chapter 12, are used primarily as hypnotics. Excessive stimulation of the cerebral cortex can cause convulsions and other types of seizures. When administered parenterally, benzodiazepines exert an anticonvulsant effect on the cerebral cortex and are very effective in stopping convulsions. They are believed to exert the anticonvulsant effect by increasing the inhibitory actions of GABA. Diazepam (Valium), lorazepam (Ativan), and clonazepam (Klonopin) are the benzodiazepines that are considered to be the drugs of choice to stop convulsions. In these situations, drugs are administered by IM or IV injection.
Benzodiazepines are well absorbed from the GI tract, and oral administration is the normal route. Diazepam, chlordiazepoxide, and lorazepam also can be given IM or IV when a rapid response is required. The main differences among the various benzodiazepines are in the duration of action. The benzodiazepines are divided into two groups: the long acting and the short acting ( Table 13:2). The long-acting benzodiazepines have half-lives of more than 20 hours. Also, during metabolism by the liver, they form active metabolites, which generally have long half-lives. When taken on a daily basis, these drugs produce effects that can last several days, due to accumulation of active metabolites in the body. Eventually, the active metabolites are conjugated with glucuronic acid. This step inactivates them and allows them to be excreted in the urine. The short-acting benzodiazepines have half-lives that range from 5 to 20 hours. Either they do not form active metabolites, or, if they do, the active metabolites do not contribute significantly to the pharmacological effect.
Clinical Indications The antianxiety drugs are used to relieve nervous tension and anxiety caused by neuroses or other life situations. Patients are made calm and relaxed without being excessively sedated. This state of mind is desirable before surgery, and antianxiety drugs are widely used as preoperative medications. The antianxiety drugs also are used to produce skeletal muscle relaxation in various musculoskeletal disturbances, as anticonvulsant and antiepileptic drugs, and as sedatives and hypnotics. Diazepam and chlordiazepoxide also are used in alcohol withdrawal, where they prevent the withdrawal syndrome and aid in the treatment of alcoholism.
Adverse Effects The most frequent side effects are drowsiness, confusion, ataxia, minor GI disturbances (nausea and constipation), Chapter 13 • Antipsychotic and Antianxiety Drugs
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and rashes. Patients should be warned that performance in operating machinery may be impaired, especially driving an automobile. Elderly individuals are more susceptible to the CNS depressant effects of these drugs. Other adverse effects, which occur with less frequency, include menstrual irregularities, changes in libido, agranulocytosis (decrease in nongranulated leukocytes), and changes in liver function. Chronic use of benzodiazepines, especially at higher dosages, may interfere with memory and recall of events.
Drug Dependency There is increasing recognition of the liability of patients to become dependent on the antianxiety drugs.This problem occurs with patients who have been taking an antianxiety drug for a long time and for whom use is abruptly terminated. Hyperactivity, tremors, nervousness, and increased anxiety are common findings. Patients are usually weaned off the benzodiazepines when the decision to stop therapy has been determined. There are also individuals who abuse the benzodiazepines (nonmedical use), consume larger-than-therapeutic doses, and develop a more severe drug dependency. These individuals exhibit hyperexcitability, tremors, and anxiety and may experience a more intense withdrawal reaction that can include the development of seizures. An important point to remember is that antianxiety drugs are not curative. They only allay the symptoms and help patients manage until the real cause of the anxiety is discovered and eliminated. Too often, antianxiety drugs are used as a crutch to avoid the discomforts of stress or personal unhappiness.
Cautions and Contraindications Pregnancy The benzodiazepines used for the treatment of anxiety have been designated FDA Pregnancy Category D, and should be avoided during pregnancy.
Drug Interactions Additive effects occur with other CNS depressants, such as the barbiturates and in particular with alcohol. Several cases of coma and permanent brain damage have occurred after the simultaneous ingestion of diazepam and alcohol. Cimetidine (Tagamet) inhibits the microsomal drug metabolizing enzymes and has been shown to inhibit the metabolism of diazepam and other benzodiazepines. When taken together, the effects of the benzodiazepines are increased and prolonged.
Use of Flumazenil (Romazicon) Flumazenil is a benzodiazepine receptor antagonist that may be administered intravenously to reverse the 182
Patient Administration and Monitoring Monitor vital signs and patient response during parenteral administration. Explain to patient the common side effects: sedation, dry mouth, mental confusion, and GI disturbances. Warn patient not to drive or attempt hazardous activities during treatment. Warn patient not to take alcohol, barbiturates, and other CNS depressants unless authorized by his or her physician. Instruct patients to report excessive sedation, mental disturbances, or loss of memory.
depressant effects of the benzodiazepine drugs. It can be used in the management of benzodiazepine overdose to antagonize the effects of excessive CNS and respiratory depression. Flumazenil also may be used in cases where one of the benzodiazepines has been administered to induce anesthesia. Midazolam (Versed) is an injectable benzodiazepine anesthetic (see Chapter 18) often used for induction of general anesthesia or for short medical procedures like endoscopy where the state of “conscious sedation” is desired. In this condition, the patient is awake but sedated to the point where unpleasant procedures can proceed without discomfort. Flumazenil is then used to reverse the effects of midazolam after the procedure is completed. In individuals who are dependent on benzodiazepine drugs (chronic use or abuse), flumazenil may precipitate a withdrawal reaction and, in some cases, seizures.
Buspirone (BuSpar) Buspirone is a drug that is used primarily as an antianxiety drug. It does not demonstrate useful sedative, hypnotic, anticonvulsant, or skeletal muscle relaxant actions like the benzodiazepines. The usual dosage for anxiety is 5–10 mg administered 2–3 times daily. Although the mechanism of action is still unclear, buspirone appears to produce its antianxiety effect by acting on serotonin receptors. Serotonin is a neurotransmitter in the brain involved in the regulation of anxiety. Anxiety is increased by high levels of serotonin. By binding to and blocking certain serotonin receptors, buspirone reduces the activity of serotonin and the level of anxiety. The potential for the development of drug tolerance and dependency with buspirone is low. Common adverse effects include dizziness, lightheadedness, rash, and
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tiredness. Buspirone is classified as an FDA Pregnancy Category B drug. In general, buspirone is well tolerated and there appear to be few contraindications for its use. It serves as a suitable alternative to the benzodiazepines, especially when drug dependence and drug abuse problems with the benzodiazepines are an issue. Buspirone is indicated mainly for the treatment of general anxiety disorder (GAD). Some individuals display a high level of anxiety and nervousness about life in general and this is classified as GAD.
Preferred Therapy for Anxiety Disorders The benzodiazepines are usually the drugs of choice for treatment of general anxiety disorder (GAD) and
panic disorder. Depending on the degree of anxiety and patient profile, the preferred drugs are usually one of the long-acting drugs such as diazepam (Valium) and chlordiazepoxide (Librium) or one of the shorter-acting drugs such as alprazolam (Xanax) or lorazepam (Ativan). Other drug classes are also effective in the treatment of anxiety disorders. The selective serotonin reuptake inhibitors (SSRIs, Chapter 14) are antidepressant drugs also effective for most types of anxiety. They are usually preferred for treatment of obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD). Tricyclic antidepressants (TCAs, Chapter 14) also are useful in treating GAD, panic disorder, and OCD. The TCAs cause more side and adverse effects than the SSRIs and are less preferred.
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Chapter Review Understanding Terminology Answer the following questions. 1. Explain the terms antipsychotic and antianxiety. (LO 13.1, 13.6) 2. What is the difference between akathisia and dystonia? (LO 13.2) 3. Define the term parkinsonism. (LO 13.2) Match the definition or description in the left column with the appropriate term in the right column. (LO 13.1, 13.2, 13.6) ___ 4. A condition characterized by muscular rigidity, tremors, and disturbances of movement.
a. akathisia
___ 5. A major form of psychosis.
c. antipsychotic drugs
___ 6. A condition causing individuals to have continuous body movement.
d. GABA
___ 7. Drug-induced involuntary movements of the lips, jaw, tongue, and extremities.
e. parkinsonism
___ 8. Drugs used to treat schizophrenia.
b. antianxiety drugs
f. tardive dyskinesia g. schizophrenia
___ 9. Drugs used to calm and reduce excessive nervousness. ___ 10. An inhibitory neurotransmitter in the CNS.
Acquiring Knowledge Answer the following questions. 1. Describe the areas of the brain and neurotransmitters that are involved in psychosis. (LO 13.1) 2. What is the mechanism of action of the phenothiazine antipsychotic drugs? (LO 13.2) 3. List the main classes of antipsychotic drugs and give an example of each. (LO 13.2, 13.3, 13.4, 13.5) 4. What pharmacological properties do the phenothiazines possess, and how do these properties relate to clinical use and adverse effects? (LO 13.2) 5. Describe a few of the more serious neurological adverse effects of the phenothiazine drugs. (LO 13.2) 6. List the major sites of action of the benzodiazepines and the clinical effects produced at each site. (LO 13.6) 7. Describe the clinical uses of diazepam (Valium). (LO 13.6) 8. List the adverse effects and drug interactions that may occur with the antianxiety drugs. (LO 13.6)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. For each adult patient described, identify a suitable drug for treatment. a. Patient A has been brought to the emergency room (ER) exhibiting extremely agitated and manic behavior. (LO 13.3) b. Patient B is in intensive care following an episode of bizarre delusions and hallucinations. (LO 13.2) c. Patient C has suffered severe anxiety ever since being diagnosed with a terminal illness. (LO 13.6) d. Patient D just presented at the ER with tonic-clonic epileptic convulsions in progress. (LO 13.6) e. Patient E has open-heart surgery scheduled for tomorrow and is experiencing presurgical anxiety. (LO 13.6) f. Patient F is in alcohol withdrawal in the local Veterans Administration (VA) hospital detoxification unit. (LO 13.6)
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2. Each of the following patients is suspected of having adverse effects to a drug prescribed for psychosis or neurosis. Identify the type of drug most likely involved in each case. a. Patient A has been experiencing dry mouth, constipation, and EPS. (LO 13.2) b. Patient B complains of a rash, nausea, drowsiness, confusion, and poor coordination (ataxia). (LO 13.6) c. Patient C presents with high fever and muscular rigidity and appears unable to move. (LO 13.2)
Multiple Choice Use you critical-thinking skills to answer the following questions. 1. The main action of phenothiazines in the treatment of schizophrenia is (LO 13.2) A. stimulation of 5HT2A receptors B. stimulation of D2 receptors C. blockage of 5HT2A receptors more than D2 receptors D. blockage of D2 receptors more than 5HT2A receptors 2. Extrapyramidal symptoms (EPS) are caused mainly by (LO 13.2) A. stimulation of GABA receptors B. stimulation of dopamine receptors C. blockage of dopamine receptors D. blockage of serotonin receptors 3. Increased triglycerides, weight gain, and diabetes are adverse effects associated with (LO 13.5) A. phenothiazines B. butyrophenones C. thioxanthenes D. atypical drugs 4. The site of action of diazepam (Valium) to relieve anxiety is the (LO 13.6) A. spinal cord B. limbic system C. reticular formation D. basal ganglia 5. The antianxiety effect of buspirone (BuSpar) is associated with (LO 13.6) A. stimulation of DA receptors B. stimulation of serotonin receptors C. blockage of serotonin receptors D. blockade of dopamine receptors 6. Flumazenil (Romazicon) is used to reverse the depressant effects of (LO 13.6) A. clozapine (Clozaril) B. alprazolam (Xanax) C. haloperidol (Haldol) D. chlorpromazine (Thorazine)
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. What are the main goals of antipsychotic drug therapy? (LO 13.1) A. increase dopamine B. block the D2 receptor C. decrease serotonin D. increase akathisia Chapter 13 • Chapter Review
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Chapter Review Continued 2. Select the additional effects of phenothiazine drugs. (LO 13.2) A. antiemetic B. anticholinergic C. antihistaminic D. antitussive 3. Select the advantages of butyrophenones over phenothiazines. (LO 13.3) A. greater incidence of antihistaminic activity B. suppression of motor tics C. greater movement disturbances D. lower incidence of EPS 4. Select the adverse effects of atypical antipsychotics. (LO 13.5) A. postural hypotension B. dermatitis C. obstructive jaundice D. weight gain 5. What are the main areas at which benzodiazepines exert their effects? (LO 13.6) A. limbic system B. cerebral cortex C. hypothalamus D. medulla oblongata
Sequencing Place the following in order from most serious to least serious adverse effects. (LO 13.2) ____________________
____________________
____________________
Most Serious
____________________ Least
neuroleptic malignant syndrome akathisia dry mouth tardive dyskinesia
Classification Place the following drugs in their appropriate classification. (LO 13.2, 13.5, 13.6) triazolam thioridazine risperidone trifluoperazine oxazepam
Phenothiazines
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olanzapine chlordiazepoxide chlorpromazine aripiprazole
Benzodiazepines
Atypical antipsychotics
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Labeling Fill in the missing labels. (LO 13.2, 13.3, 13.4, 13.5) Nerve ending
High-potency blocking drugs
DA
Receptors
Drug effect
Fluphenazine Haloperidol Thiothixene D2
(higher incidence of EPS)
(a) Dopaminergic
5HT
Aripiprazole Olanzapine Risperidone
(lower incidence of EPS) 5HT2A
(b) Serotonergic
ACH
Chlorpromazine Thioridazine Clozapine Cholinergic
(c) Cholinergic
NE
Chlorpromazine Thioridazine Clozapine ␣-Adrenergic
(d) Adrenergic
H
Chlorpromazine Thioridazine Clozapine Histamine-1
(e) Histaminergic
For interactive animations, videos, and assessment, visit:
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Chapter 14
DRUG CLASS AT A GLANCE OTC
NO
PRESCRIPTION
YES
SCHEDULED DRUGS
NO
FDA PREGNANCY CATEGORY
B,C,D (lithium)
INDICATIONS Mental depression, mania, bipolar disorder
Antidepressants, Psychomotor Stimulants, and Lithium KEY TERMS bipolar mood disorder: mood disorder where episodes of mania and depression occur alternately. depression: mental state characterized by depressed mood, with feelings of frustration and hopelessness. exogenous, or reactive, depression: depression caused by external factors or life events. lithium: an element similar to sodium that is used in the treatment of mania and bipolar mood disorder. major depressive disorder (MDD): depression that arises from within an individual and requires psychotherapy and drug treatment. mania: mental state of excitement, hyperactivity, and excessive elevation of mood. monoamine oxidase (MAO): enzyme that inactivates norepinephrine and serotonin. Monoamine Theory of Mental Depression: theory that mental depression is caused by low brain levels of norepinephrine and serotonin (monoamines). psychomotor stimulant: amphetamine or related drug that increases mental and physical activity. SSRIs: selective serotonin reuptake inhibitors, a class of antidepressant drugs. TCAs: tricyclic antidepressants, a class of antidepressant drugs.
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Learning Outcomes
After studying this chapter, you should be able to
14.5 explain the mechanism of action of the MAO inhibitors and describe the adverse effects and dietary restrictions relating to these drugs.
14.1 identify the different types of depression and the importance of neurotransmitter function in the cause and treatment of depression.
14.6 discuss the use of psychomotor stimulants in the treatment of narcolepsy, hyperkinetic syndrome, and obesity.
14.2 describe the mechanism of action and adverse effects profile of the selective serotonin reuptake inhibitors (SSRIs). 14.3 explain the major difference between the SSRIs and the atypical SSRI antidepressants. 14.4 describe the mechanism of action and the adverse effects profile of the tricyclic antidepressants (TCAs).
14.7 explain the use of lithium in mania and bipolar disorder and the adverse effects associated with its use. 14.8 identify the preferred therapies for depression, mania, and bipolar disorder.
Introduction
Mental depression is a common illness that affects most people at one time or another. During depression, there are changes in mood and behavior, along with feelings of frustration and hopelessness. Decreased appetite and difficulty in sleeping are also common signs of depression. Depressed individuals appear unable to cope with the demands or stresses of living. In severe depression, when a person feels there is no escape, he or she may come to think of suicide as an acceptable solution. Early recognition and treatment are essential for prevention of the serious consequences of depression. Evidence accumulated over the years indicates that deficiencies of norepinephrine (NE) and serotonin (5HT) in the brain are involved in the cause of mental depression. Drugs that increase levels of NE and 5HT are used to treat depression. The causes of mood disorders such as mania and bipolar disorder are not clearly understood. It is believed that hyperactivity in certain areas of the brain and excessive activity of neurotransmitters may be involved. These conditions often require a combination of drug therapies.
LO 14.1
TYPES OF DEPRESSION There are several different types of depression. Depression that is caused by external factors (death or unemployment) is referred to as exogenous, or reactive, depression. Usually, there is a period of shock and depression, which is followed by a period of readjustment and a resolve that life must go on. In this sense, a reactive depression is self-limiting and usually does not require drug therapy. The love and understanding of family or friends support the individual through the crisis.
The second major type of depression is referred to as major depressive disorder (MDD). MDD is frequently more serious and usually requires both psychotherapy and drug treatment. This type of depression originates from within the individual and may not be associated with easily recognized causes. Psychological disturbances and maladjustments or biochemical defects in the brain are thought to be involved. Episodes of MDD may occur at intervals throughout one’s lifetime. In some cases of depression, there are alternate periods of hyperexcitability and elation known as mania. Individuals who experience these alternating Chapter 14 • Antidepressants, Psychomotor Stimulants, and Lithium
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Figure 14.1 Illustration of the Site and Mechanism of Action of the SSRIs, Atypical SSRIs, and Tricyclic Antidepressants to Block the Reuptake of Serotonin (5HT) Back into Serotonergic Nerve Endings Serotonergic nerve ending
Synaptic cleft
Neuronal membrane
5HT 5HT 5H H MA M MAO AO A O
Serotonin receptors
5HT
The psychomotor stimulants are generally amphetamines or amphetamine-like drugs that produce a generalized CNS stimulation, usually increased wakefulness and alertness. These drugs are not true antidepressants and have limited therapeutic uses. Lithium is referred to as a mood stabilizer and is used to treat individuals who experience wide shifts of mood, mania, or the alternating cycles of depression and mania (bipolar mood disorder). Some anticonvulsant drugs (Chapter 16) are also effective in treating mania and bipolar disorder.
Selective Serotonin Reuptake Inhibitors (SSRIs)
The SSRIs are a group of drugs that have a very selective action to block the reuptake of serotonin Inactive (5HT) back into the serotonergic nerve endings. metabolite This action increases the concentration of 5HT in the synaptic cleft, which results in increased stimulation of serotonin receptors (Figure 14.1). This action increases the concentration of 5HT in the synaptic The increase in 5HT activity in the limbic and cleft, resulting in increased stimulation of serotonergic receptors in the brain. cerebral cortical areas of the brain is believed to contribute to the antidepressant effect. The cycles of depression and mania are classified as manicSSRIs usually stimulate and activate CNS activity. Howdepressive. Another term for this condition is bipolar ever, there are differences among the SSRI drugs in the mood disorder. degree of CNS activation; fluvoxamine is an exception and produces a sedating effect. Fluoxetine was the first SSRI to be introduced and it will be discussed in more LO 14.2 2 LO 14.3 3 LO 14.4 4 LO 14.5 detail. The other SSRIs produce similar actions and are compared in Table 14:1. DRUGS USED TO TREAT Fluoxetine is well absorbed after oral administraDEPRESSION tion. It is metabolized in the liver into an active metaboAn important advance in understanding depression lite that has a half-life that ranges from several days to a occurred with the discovery that the levels of norepiweek or more. The metabolites are primarily excreted nephrine and serotonin (5HT) in the brain can influin the urine. Fluoxetine also has been shown to be an ence mental behavior. Low levels of norepinephrine inhibitor of the metabolism of other drugs such as antiand/or serotonin are associated with mental depression, coagulants and benzodiazepines. while high levels of norepinephrine and/or serotonin may be involved in mania. This concept involving norClinical Indications epinephrine and serotonin (referred to chemically as The SSRIs have become preferred therapy for treatment monoamines) is known as the Monoamine Theory of of major depression. All SSRIs are usually administered Mental Depression. 1–2 times per day. SSRIs are also effective in the treatment Drugs that can increase the level of norepinephrine of most anxiety disorders such as posttraumatic stress disor serotonin in the brain are useful in the treatment order (PTSD) and obsessive-compulsive disorder (OCD). of mental depression. They are referred to as antideIn OCD, individuals have repetitive and excessive impulses pressants, or mood elevators. The major antidepressant to perform some physical or behavioral action. These drug classes include the selective serotonin reuptake impulses can interfere with and disrupt the normal daily inhibitors (SSRIs), atypical SSRIs, tricyclic antideroutine of work and living. Fluoxetine and sertraline also pressants (TCAs), and monoamine oxidase inhibitors are approved for premenstrual dysphoric disorder, where (MAOIs). mood disturbances occur in relation to the menstrual cycle. Bl Block reuptake SSRIs Atypical SSRIs Tricyclics (TCAs)
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Adverse Effects
Table 14:1 Unlike the tricyclic antidepressants, the SSRIs have little action to block cholinergic, Selective Serotonin Reuptake Inhibitors adrenergic, or histamine receptors. Consequently, SSRIs and atypical SSRIs (see below) CNS activation Drug (Trade Name) Daily dosage range produce fewer side and adverse effects, and currently have become the most widely used Low Citalopram (Celexa) 20–40 mg PO antidepressant drugs. 10–20 mg PO Escitalopram (Lexapro) Low All the SSRIs listed cause GI disturbances including nausea, diarrhea, dry mouth, and Fluoxetine (Prozac) 20–40 mg PO High anorexia. SSRIs also have been associated with sexual dysfunction, most commonly Fluvoxamine (Luvox) 50–200 mg PO Sedating reduced sexual interest and delayed orgasm. Other CNS effects include headache, nerParoxetine (Paxil ) 20–40 mg PO Low vousness, insomnia, and tremors. The most common symptoms of overSertraline (Zoloft) 50–200 mg PO Low dosage include confusion, fever, tremor agitation, restlessness, and other signs of CNS excitation; seizures also have been reported. These symptoms are referred to as the “seroFigure 14.2 tonin syndrome” and may lead to coma and death if not treated. Sudden discontinuation of SSRI Illustration of the Site and Mechanism of Action of treatment has been associated with a discontinua- Atypical SSRIs and Tricyclic Antidepressants to Block the tion syndrome. Symptoms include dizziness, nau- Reuptake of Norepinephrine (NE) Back into the Adrenersea, insomnia, and anxiety. The dosage of SSRIs gic Nerve Ending and related drugs should be gradually reduced Adrenergic nerve ending Synaptic cleft Neuronal membrane over time when treatment is stopped.
Atypical SSRI Antidepressants
NE Adrenergic
receptors The atypical SSRI antidepressant drugs block NE N reuptake of serotonin like the SSRIs but have NE additional actions on other neurotransmitters MA M MAO AO A O and receptors ( Figures 14.1 and 14.2). These drugs have been classified by different names and chemical classifications; they will be referred Block reuptake Bl to in this text as atypical SSRI antidepressants. Atypical SSRIs Inactive Tricyclics (TCAs) Like the SSRIs, they have little effect in blocking metabolite cholinergic, adrenergic, or histamine receptors. The atypical drugs affect serotonin and other This action increases the concentration of NE in the synaptic neurotransmitters such as norepinephrine and cleft resulting in increased stimulation of adrenergic receptors dopamine. The pharmacologic actions of these in the brain. drugs are complex; only the main features are presented. The atypical SSRI antidepressants are listed in Table 14:2. switch over into mania. Bupropion is highly activatThe major pharmacologic actions of bupropion ing and and may cause seizures. Bupropion also is pre(Wellbutrin) are to increase the release of and inhibit the scribed for patients who are trying to quit the smoking reuptake of norepinephrine and dopamine. Bupropion habit. Nefazodone (Serzone) and trazodone (Desyrel) are has minimal effect to inhibit the reuptake of serotonin. drugs that are weak reuptake inhibitors of serotonin The antidepressant effects are useful in the treatment and norepinephrine but potent antagonists of seroof bipolar disorder, where it is claimed to prevent the tonin 5HT2A receptors. This action also provides some
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Table 14:2
Atypical SSRI Antidepressant Drugs Drug (Trade Name)
Daily dosage range
CNS activation
Bupropion (Wellbutrin)
150–450 mg PO
High
Desvenlafaxine (Pristiq)
50–200 mg PO
Moderate
Duloxetine (Cymbalta)
40–60 mg PO
Low
Mirtazapine (Remeron)
15–45 mg PO
Sedating
Nefazodone (Serzone)
100–600 mg PO
Sedating
Trazodone (Desyrel )
200–600 mg PO
Sedating
Venlafaxine (Effexor)
75–375 mg PO
Moderate
antipsychotic activity. Adverse effects include sedation, orthostatic hypotension, and liver toxicity. Trazodone also is associated with priapism, which is the development of sustained and painful penile erections. Venlafaxine (Effexor), desvenlafaxine (Pristiq), and duloxetine (Cymbalta) are drugs that block the reuptake of both serotonin and norepinephrine. Venlafaxine is moderately activating and has adverse effects similar to the SSRIs. Increases in diastolic blood pressure are evident at higher doses. Desvenlafaxine is the active metabolite of venlafaxine and has similar properties. Duloxetine causes low CNS activation; adverse effects include GI disturbances, insomnia, and feelings of weakness and fatigue. The actions of mirtazapine (Remeron) include the increased release of norepinephrine and serotonin, blockade of 5HT2 and 5HT3 receptors, and potent histamine receptor blocking actions. Mirtazapine is sedating and usually does not cause GI disturbances or sexual dysfunction. Weight gain has been associated with this drug.
Tricyclic Antidepressants Tricyclic antidepressant drugs (TCAs or tricyclics) are so named because of the characteristic triple-ring structure that they possess. Recently, some new antidepressants, which produce pharmacological effects similar to those of the tricyclics, have been introduced with two rings (bicyclics), four rings (tetracyclics), and others with quite different chemical structures (nontricyclics).
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The chemistry of these antidepressants is beyond the scope of this book. However, a simple method of classification involves the chemical substitutions (usually methyl groups) on the nitrogen molecule, which is present in all of the drugs. Most of the drugs can then be classified as being either secondary amines (two substitutions on the nitrogen) or tertiary amines (three substitutions on the nitrogen). Another interesting generalization is that secondary amines mainly increase brain levels of norepinephrine more than serotonin while the tertiary amines mainly increase brain levels of serotonin more than norepinephrine. The key to effective therapy is to identify which neurotransmitter should be increased in each patient; however, this step is not always easy. Frequently, several drugs must be tried with each patient before the most effective drug is found.
Mechanism of Action The main action of the tricyclics and related antidepressant drugs is to block the reuptake of norepinephrine and serotonin back into the neuronal nerve endings. As a result there is an accumulation of these neurotransmitters in the synaptic clefts ( Figures 14.1 and 14.2). This action increases the level of neuronal activity of norepinephrine and serotonin and alleviates the symptoms and dysfunction of depression. The pharmacological actions occur within a few hours of administration. However, the full antidepressant effect requires 2 to 4 weeks to develop. Consequently, it is believed that tricyclics and related antidepressant drugs may produce additional pharmacologic actions that are not yet completely understood. However, increasing the concentrations of norepinephrine and serotonin in the brain does appear to be involved in the antidepressant effect.
Pharmacological Actions In addition to the antidepressant effect, the tricyclics and related drugs produce varying degrees of sedation, anticholinergic effects, and alpha-adrenergic blockade. The degree of sedation, anticholinergic, and alphablocking effects among the various drugs is compared in Table 14:3. Generally, the tertiary amines produce more sedation than do the secondary amines. Sedation is often a valuable effect, especially in patients who suffer
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drug interaction. Tricyclic and related antidepressants are listed in Table 14:3.
Note to the Health Care Professional
Adverse and Toxic Effects
Since suicidal tendencies are associated with depression, ensure that patients have access to only a limited supply of antidepressant drugs. Attempts at suicide may be increased during initial treatment as the patient becomes more mentally and physically activated. Encourage the patient to engage in physical and social activities that can stimulate motivation and lend emotional support.
The tricyclics possess significant anticholinergic activity, which is responsible for many of the adverse effects. Anticholinergic effects include dry mouth, constipation, urinary retention, and rapid heartbeat. Alpha-blocking actions may cause postural hypotension, blurred vision, and drowsiness. Like the MAO inhibitors, the tricyclics stimulate the CNS and may produce restlessness, tremors, convulsions, or mania. In addition, the tricyclics may produce toxic effects in the heart and liver. In the heart, the effects can be detected by an electrocardiogram. Alterations in the T wave and ST segment, which may lead to serious cardiac arrhythmias, are the most common changes. In the liver, the tricyclics may cause an obstructive type of jaundice, which is relieved when drug treatment ends. One of the dangers of antidepressant drug treatment is the risk of patients attempting suicide by overdosing on antidepressant drugs. In toxicity the anticholinergic effects, alpha-blocking effects, cardiac disturbances, and CNS stimulation of the TCAs can result in lethal cardiac arrhythmias, seizures, and death.
insomnia along with their depression. The anticholinergic and alpha-blocking effects are associated with many of the side effects of these drugs. The tricyclics, like the MAO inhibitors discussed later, require 2 to 4 weeks to produce their maximum effect. The antidepressant effects of the tricyclics also continue for approximately 2 weeks after drug administration is terminated. Therefore, extreme caution should be exercised when patients are switched from MAO inhibitors to tricyclics, or vice versa, to prevent
Table 14:3
Representative Tricyclic and Related Antidepressants Drug (Trade Name)
Sedation
AC
Alpha blockade
Daily dosage range
Clomipramine (Anafranil )
High
High
High
150–250 mg PO
Desipramine (Pertofrane)
Low
Low
High
75–200 mg PO
Nortriptyline (Aventyl)
Moderate
Moderate
Moderate
50–150 mg PO
Amitriptyline (Elavil )
High
High
High
75–300 mg PO
Doxepin (Sinequan)
High
High
High
75–300 mg PO
Imipramine (Tofranil )
Moderate
Moderate
High
75–300 mg PO
Secondary amines
Tertiary amines
AC—Anticholinergic activity; alpha blockade reflects postural hypotension
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Table 14:4
Drug Interactions of Tricyclic Antidepressants Tricyclics with
Response
Alcohol
Increased sedation
Amphetamines
Increased CNS stimulation
Anticholinergics, antihistamines
Dry mouth, constipation, urinary retention, blurred vision
Anticonvulsants
Increased possibility of seizures
Barbiturates
Increased metabolism of tricyclics (decreased effectiveness), increased sedation
MAO inhibitors
Increased CNS stimulation, hyperpyrexia, seizures
Phenothiazines
Anticholinergic effects, CNS depression
Drug Interactions The tricyclic antidepressants interact with a number of other drugs, as indicated in Table 14:4.
MONOAMINE OXIDASE INHIBITORS Monoamine oxidase (MAO) is an enzyme found in most body cells but particularly in the adrenergic and serotonergic nerve endings. The normal function of MAO is to break down norepinephrine and serotonin into metabolites that are then excreted by the kidneys. MAO prevents the buildup of excessive levels of norepinephrine and serotonin in the brain and other body tissue. In mental depression, there appears to be an abnormal decrease in the levels of brain norepinephrine and serotonin. Drugs that inhibit, or block, MAO are called appropriately MAO inhibitors. By inhibiting MAO, these drugs decrease the amounts of norepinephrine and serotonin that are destroyed. Consequently, the MAO inhibitors permit the levels of norepinephrine and serotonin in the brain to increase. This increase is usually accompanied by clinical improvement of the depression. Like the TCAs, the MAO inhibitors require 2 to 4 weeks to produce their maximum effect. After a week or so of treatment, there is usually an improvement in appetite and sleep, followed by an elevation of mood and an overall improvement in mental state. These effects continue 194
for approximately 2 weeks after termination of treatment. The MAO inhibitors are infrequently used today and primarily indicated when other antidepressant drugs are not effective. The MAO inhibitors are involved in many drug interactions. Caution must be exercised if other drugs, especially other antidepressants, are administered during administration of MAO inhibitors and while MAO inhibitors remain in the system. Serious drug interactions can occur.
Dietary Restrictions One of the main disadvantages of MAO inhibitor therapy is the dietary restrictions. Many foods contain a substance known as tyramine, which causes the release of norepinephrine from storage granules located inside the adrenergic nerve endings. When MAO is inhibited, tyramine may produce a massive release of norepinephrine, which can result in serious consequences, such as hypertensive crisis or cerebral stroke. Foods that normally contain tyramine include wine, beer, herring, and certain cheeses. In addition, certain sympathetic drugs used in the treatment of cold symptoms (decongestants and bronchodilators) interact with the MAO inhibitors, causing potentiation of the effects of the sympathetic agents. Patients receiving MAO inhibitors must be thoroughly instructed with regard to the foods and other medications to avoid. The most frequently used MAO inhibitors are listed in Table 14:5.
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Table 14:5
Monoamine Oxidase (MAO) Inhibitors Drug (Trade Name)
Daily dosage range
Isocarboxazid (Marplan)
10–20 mg PO
Phenelzine (Nardil)
45–90 mg PO
Tranylcypromine (Parnate)
30–60 mg PO
In addition to mental stimulation, amphetamines stimulate motor, or physical, activity. This stimulation causes individuals who are trying to delay fatigue and stay awake to use amphetamines inappropriately. Amphetamine stimulation of the CNS is also associated with a decrease in appetite, and weight reduction presents another area of amphetamine abuse. Because the therapeutic benefits of amphetamines are low and the abuse potential high, there are very few situations where use of amphetamines is warranted.
Mechanism of Action Adverse Effects The MAO inhibitors are capable of producing a wide variety of adverse effects. Common adverse effects include dry mouth, urinary retention, constipation, blurred vision, hypotension, weight gain, and sexual dysfunction. A variety of CNS disturbances including restlessness, dizziness, insomnia, tremors, and seizures may occur. These effects are intensified with overdosage. In addition, they can produce a type of liver damage that may be fatal. Because of the high incidence of adverse effects, many physicians believe that these drugs should be reserved for patients who do not respond to other antidepressant drugs.
LO 14.6
PSYCHOMOTOR STIMULANTS The psychomotor stimulants include the amphetamines and other closely related drugs, which are really not classified as antidepressants. Their role in the treatment of depression is extremely limited. Because of the delayed therapeutic effects of MAO inhibitors and tricyclics, psychomotor stimulants are occasionally used during the first few weeks of treatment to elevate mood and increase psychomotor activity. Amphetamines also are used to treat narcolepsy (uncontrolled tendency to fall asleep) and hyperkinesis in children. Amphetamines stimulate the reticular formation, which increases wakefulness and alertness and reduces the number of attacks of narcolepsy. In hyperkinetic children, amphetamines increase alertness and attention span, which are important in improving learning ability. Also, amphetamines seem to calm down the hyperactivity. This result is opposite to what would be expected and is referred to as a paradoxical effect. The reason for this effect is not fully understood.
The amphetamines stimulate the CNS by increasing the activity of norepinephrine and dopamine in the brain. Amphetamines increase neurotransmitter activity by several different mechanisms. They act directly to stimulate norepinephrine and dopamine receptors, they stimulate the release of norepinephrine and dopamine from the nerve endings, and they inhibit the reuptake of these neurotransmitters back into the nerve endings. These actions produce CNS stimulation and an elevation of mood. Psychomotor stimulants are listed in Table 14:6, but it should be emphasized that the psychomotor stimulants are not true antidepressant drugs and their use as such is extremely limited. Amphetamines have the disadvantage of producing drug tolerance and drug dependence. The amphetamines are among the leading “street drugs” that are abused and illegally marketed. Drug abuse of amphetamines is discussed in Chapter 15.
Adverse and Toxic Effects The psychomotor stimulants increase the activity of the sympathetic nervous system, producing dry mouth,
Table 14:6
Psychomotor Stimulant Drugs Drug (Trade Name)
Daily dosage range
Amphetamine
10–60 mg PO
Dexmethylphenidate (Focalin)
5–20 mg PO
Dextroamphetamine (Dexedrine)
5–30 mg PO
Methamphetamine (Desoxyn)
5–60 mg PO
Methylphenidate (Ritalin)
10–60 mg PO
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Patient Administration and Monitoring Selective Serotonin Reuptake Inhibitors
Remember that these drugs may be contraindicated in patients with glaucoma and prostatic hypertrophy, and that the elderly are more sensitive to anticholinergic drugs.
Explain to patient the common side effects: headache, nervousness, insomnia, nausea, loss of appetite, diarrhea.
Instruct patient not to take other drugs unless this is checked with the physician or pharmacist.
Instruct patient to report excessive GI and CNS stimulation (agitation, seizures).
MAO Inhibitors
Instruct patient not to suddenly stop taking these drugs on his or her own.
Tricyclic Drugs
Provide patient with a list of tyramine-containing foods and over-the-counter drugs that must be avoided while taking MAO inhibitors.
Monitor vital signs when drugs are administered parenterally with particular attention to blood pressure and heart rate.
Explain to patient the common side effects: dizziness, low blood pressure, dry mouth, constipation and other GI disturbances, blurred vision, impotency in males.
Explain to patient the common side effects due to anticholinergic, alpha-blocking, and antihistaminic actions: dry mouth, constipation, low blood pressure, drowsiness.
Instruct patient to report excessive dizziness or feelings of faintness, difficulty with urination, CNS stimulation or agitation, yellowing of skin (liver jaundice).
Instruct patient to report increased pulse rate, excessive difficulties with urination or defecation, excessive CNS stimulation (tremors, restlessness, seizures).
rapid heartbeat, increased blood pressure, restlessness, and insomnia. Toxic doses may produce severe agitation and a paranoid type of psychosis. LO 14.7
LITHIUM Lithium is used for the treatment of mania and bipolar mood disorder. It is often used in combination with antidepressant drugs in the manic-depressive or bipolar form of psychosis. In mania, there appears to be an excess of norepinephrine and possibly other monoamines (opposite to the situation in depression) in the brain, which produces excitement, hyperactivity, and excessive elevations of mood. Mania is characterized by periods of hyperactivity and excitement combined with excessive elevations of mood. Manic individuals are usually very talkative, but their thoughts and ideas are most often unrealistic. Lithium appears to reduce the hyperactivity and the excitement and also allows better organization of thought patterns. Several anticonvulsant drugs, including vaproate, carbamazepine, and lamotrigine, also provide mood stabilizing effects and are used in the treatment of mania and bipolar disorder.These drugs are discussed in Chapter 16.
Both lithium (Li+) and sodium (Na+) exist in body fluids as charged particles, or ions. However, whereas Na+ is normally required for conduction of nerve impulses, Li+ interferes with nerve conduction. As a result, there is a decrease in the excitability of nerve tissue. The mechanism of action of lithium is not clearly understood. Actions that decrease the levels of norepinephrine and other transmitters have been suggested.
Pharmacokinetics Lithium is administered as a salt, lithium carbonate, in the form of capsules (Eskalith) or controlled release and slow-release tablets (Eskalith CR, Lithobid ). Usually 1 to 2 weeks of treatment are required before therapeutic effects are observed. Lithium can be an extremely toxic drug. Therefore, blood levels are periodically measured to prevent the development of excessive levels of lithium in the body. Lithium and sodium ions compete with each other for renal elimination. Adequate sodium intake is necessary for proper urinary excretion of lithium. Decreased sodium intake and hyponatremia (low sodium levels) promote the retention of lithium and can lead to toxicity.
Adverse and Toxic Effects Mechanism of Action Lithium is an element similar in chemical properties to sodium. The body utilizes lithium as if it were sodium. 196
Side effects are common with lithium, even at therapeutic doses. Initially, most patients experience some nausea or tremors that usually disappear with continued treatment.
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Patient Administration and Monitoring Explain to patient that the therapeutic effects of lithium may require 1 or 2 weeks of treatment. Explain to patient that side effects are common and usually include nausea and tremors. Explain to patient that lithium is a salt and that increased thirst and frequency of urination are common. Instruct patient on the importance of adequate fluid and sodium intake. Instruct patient to report excessive nausea or vomiting, excessive CNS stimulation, dizziness, abnormal muscle movements, low blood pressure, ringing in the ears. Explain to patient that periodic drug blood levels may be required.
With overdose, vomiting, diarrhea, drowsiness, loss of equilibrium, ringing in the ears, and frequent urination are common. At toxic levels, the heart and kidneys may be damaged, leading to the development of cardiac arrhythmias or nephritis. Therefore, extreme caution is observed when treating cardiac or renal patients. In addition, lithium occasionally produces disturbances of the thyroid gland, and it is therefore contraindicated in patients with an existing thyroid condition. In acute overdoses, muscle fasciculations, convulsions, and circulatory collapse leading to death are possible. Treatment is aimed at increasing the excretion of lithium by forcing fluids and increasing the intake of sodium.
Cautions and Contraindications Pregnancy Lithium has been designated FDA Pregnancy Category D and therefore should not be used during pregnancy.
LO 14.8
PREFERRED THERAPY FOR DEPRESSION, MANIA, AND BIPOLAR DISORDER Due to the complex nature of depression and individual variations in mental and psychological states, it is difficult to select a single drug as preferred therapy for treatment of depression. However, the SSRIs are currently considered the preferred drugs for major depression. The advantages of the SSRIs are the lower incidence of adverse and toxic effects. Unlike the TCAs, the SSRIs do not cause significant anticholinergic, alpha-adrenergicblocking, or antihistaminic actions. The atypical SSRIs are also usually preferred over the TCAs for the same reason. The atypical SSRIs also produce additional actions on other neurotransmitters and receptors that can benefit patients who are not experiencing sufficient antidepressant relief from SSRIs. The use of TCAs and MAO inhibitors has significantly decreased and these drugs mainly serve as alternates when SSRIs and related drugs are contraindicated or ineffective. The preferred treatment for mania and bipolar disorder has changed over the years. Previously lithium was the preferred drug for mania and in combination with antidepressants for bipolar disorder. However, a number of anticonvulsant drugs have shown effectiveness, particularly in bipolar disorder. These drugs cause fewer side, adverse, and toxic effects. Valproate (Depakene) is now considered to be equal to and in some bipolar conditions more effective than lithium. Currently lithium and valproate are considered the two first-line mood stabilizers. Other mood-stabilizing anticonvulsants include carbamazepine (Tegretol ) and lamotrigine (Lamictal ). Often in acute manic episodes antipsychotic drugs also are administered if there are psychotic symptoms.
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Chapter Review Understanding Terminology Answer the following questions. ___ 1.
Differentiate between mania and depression. (LO 14.1)
___ 2.
Explain the Monoamine Theory of Mental Depression. (LO 14.1)
___ 3.
List the two main types of depression and define each. (LO 14.1)
Acquiring Knowledge Answer the following questions. 1. What neurotransmitters are deficient in mental depression? (LO 14.1) 2. How do the MAO inhibitors increase the levels of norepinephrine and serotonin in the brain? (LO 14.5) 3. Explain the mechanism of action of the tricyclic antidepressants. (LO 14.4) 4. What are the main pharmacological differences between the secondary and tertiary amine antidepressants? (LO 14.4) 5. What adverse effects are associated with the tricyclic antidepressants? (LO 14.4) 6. How do the selective serotonin reuptake inhibitors produce their antidepressant effect? (LO 14.2) 7. What are the adverse effects of the selective serotonin reuptake inhibitors? (LO 14.2) 8. What are some of the clinical uses of psychomotor stimulants? (LO 14.6) 9. Explain the mechanism of action and major adverse effects of lithium. (LO 14.7) 10. Which antidepressant drug classes are considered to be the preferred therapy for depression. (LO 14.8)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. Assume that one of your duties in the mental health clinic where you work is to note for each patient any contraindications or potential drug interactions for current medications. You also assist with drug overdose emergencies. a. Patient A has been diagnosed with major depressive disorder. He’s been taking Elavil for several weeks, but it makes him excessively drowsy, so his medication is being changed to an MAO inhibitor. The patient also is taking a prescription decongestant for allergies. What should you note on the patient’s chart regarding adverse effects and drug interactions? (LO 14.4, 14.5) b. Patient B appeared at the clinic suffering from a possible overdose of lithium. She appeared drowsy and complained of dizziness and ringing in her ears. What should be done to help rid her body of the excess lithium? (LO 14.7) 2. Joe works as a volunteer on a depression hotline. What type of depression is experienced by each of the following anonymous callers? a. Caller A says he has no particular reason to feel down, but he’s feeling really depressed anyway. He says he gets down-and-out a lot, but it doesn’t usually get quite this bad. He wonders if there’s any kind of treatment or drug for how he feels. (LO 14.1) b. Caller B says she’s usually a happy-go-lucky sort of person, but she’s been feeling depressed since her mother died last month. She thinks she should be over the worst of her grief by now and wonders if she should get counseling. (LO 14.1) 3. Janet has just been prescribed lithium for her manic states. What should be included in her medication counseling? (LO 14.7) 4. Robyn’s physician has just prescribed Nardil for severe depression. What foods does Robyn need to avoid and why? (LO 14.5)
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Multiple Choice Use your critical-thinking skills to answer the following questions. 1. The main pharmacologic effect of the SSRIs is (LO 14.2) A. increase levels of norepinephrine B. increase levels of serotonin C. decrease levels of norepinephrine D. decrease levels of serotonin 2. The pharmacologic effects of TCAs include (LO 14.4) A. alpha-adrenergic blockade B. antihistaminic C. anticholinergic D. all statements are true 3. The serotonin syndrome is mainly associated with overdosage of (LO 14.2) A. tricyclic antidepressants B. monoamine oxidase inhibitors C. selective serotonin reuptake inhibitors D. psychomotor stimulants 4. The main pharmacologic effects of TCAs on neurotransmitter activity is (LO 14.4) A. increase norepinephrine B. increase acetylcholine C. increase serotonin D. all statements are true E. only A and C are true 5. Venlafaxine (Effexor) is classified as (LO 14.3) A. MAOI B. TCA C. SSRI D. atypical SSRI 6. Clinical uses of bupropion (Wellbutrin) include (LO 14.3) A. treatment of depression B. bipolar disorder C. cessation of smoking D. all statements are true 7. Serious adverse effects of TCAs include (LO 14.4) A. liver toxicity B. cardiac arrhythmias C. excess CNS stimulation D. all statements are true
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Which of the following is true of depression? (LO 14.1) A. it can be self-limiting B. treatment is aimed at increasing serotonin C. it can be caused by biochemical defects D. it may not require drug therapy to relieve Chapter 14 • Chapter Review
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Chapter Review Continued 2. Which of the following are restrictions for patients taking MAOIs? (LO 14.5) A. liver B. cheese C. beer D. tuna 3. Select the main actions of TCAs. (LO 14.4) A. block reuptake of NE B. decrease the destruction of NE C. decrease the reuptake of serotonin D. block MAOIs 4. Which of the following are true of SSRIs? (LO 14.2) A. preferred treatment for major depression B. used to treat mania disorders C. anorexia is an adverse effect D. has a half-life of 12 hours 5. Select the main pharmacologic actions of bupropion. (LO 14.3) A. maximum effect on reuptake of serotonin B. decreases release of NE C. promotes the reuptake of NE D. inhibits reuptake of dopamine
Sequencing Place the following in order of CNS activation. (LO 14.3) __________________
__________________
__________________
__________________
High
Moderate
Low
Sedating
Effexor Wellbutrin Cymbalta Serzone
Classification Place each drug under the appropriate classification. (LO 14.2, 14.3, 14.4, 14.5) Elavil
Desyrel
Parnate
Remeron
Cymbalta
Celexa
Paxil
Nardil
Marplan
Zoloft
Aventyl
Sinequan
SSRI
200
TCA
MAOI
Atypical SSRI
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Matching Match the following drug classifications with their main mechanism of action. (LO 14.2, 14.3, 14.4, 14.5, 14.6, 14.7) a. monoamine oxidase inhibitors b. tricyclic antidepressants c. SSRIs d. atypical SSRIs e. psychomotor stimulants f. lithium 1. 2. 3. 4. 5. 6.
_____block reuptake of NE _____interferes with nerve conduction _____block reuptake of 5HT _____increase wakefulness _____decrease the destruction of serotonin _____increase release of NE
Documentation Using the prescription below, answer the following questions. (LO 14.7)
Wellness Clinic Practice RX 12345 Main Avenue Anytown, USA 12345 360-555-1000 NAME:
George Sims
DATE:
ADDRESS: RX
Eskalith 300mg
Sig:
1 po tid
Dr. Joanna Joans Substitution Permitted DEA #:
a. b. c. d.
M.D.
M.D. Dispense as written REFILL:
NR
1
2
3
4
For what condition is Mr. Sims most likely being treated? How long will it be before the patient sees any therapeutic effects from this treatment? What precautions or tests should the patient be taking for treatment with this drug? When is this drug contraindicated?
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Chapter Review Continued Labeling Fill in the missing labels. (LO 14.2, 14.4)
Adrenergic nerve ending
Synaptic cleft
NE E
MA MA MAO AO O
NE
For interactive animations, videos, and assessment, visit:
www.mcgrawhillconnect.com 202
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Chapter 15
Psychotomimetic Drugs of Abuse DRUG CLASS AT A GLANCE OTC
NO
KEY TERMS cannabinoid: pharmacologically active substance obtained from the marijuana plant.
PRESCRIPTION Amphetamines, nabilone, dronabinol
cross-tolerance: drug tolerance that develops between similarly acting drugs.
SCHEDULED DRUGS
dependency: requirement of repeated drug consumption in order to prevent onset of withdrawal symptoms.
I—Hallucinogens, marijuana II—Amphetamines, nabilone III—Dronabinol
FDA P REGNANCY
Amphetamines
CATEGORY
C
INDICATIONS Amphetamines—narcolepsy, hyperkinesis; Dronabinol, nabilone— antiemetic, appetite stimulant in AIDS
designer drug: chemically altered form of an approved drug that produces similar effects and that is sold illegally. drug tolerance: requirement of larger doses to be consumed in order to obtain the desired effects. flashback: phenomenon occurring long after the use of LSD in which the hallucinogenic effects are relived in some type of memory flash. hallucinogenic drug: a drug or plant substance that produces psychotomimetic effects and sensory distortions. hashish: resin from the marijuana plant that contains higher levels of THC. psychotomimetic drug: drug or substance that can induce psychic and behavioral patterns characteristic of a psychosis. synesthesia: distortion of sensory perception; usually associated with the use of LSD. tetrahydrocannabinol (THC): active ingredient of the marijuana plant.
Learning Outcomes
After studying this chapter, you should be able to 15.1 identify the mechanisms of action of hallucinogenic drugs and the psychotomimetic effects produced. 15.2 explain the dose-related hallucinogenic phases and the treatment for intoxication.
15.3 identify the mechanism of action, effects, and treatment for intoxication with psychomotor stimulants. 15.4 describe the mechanism of action, effects, and treatment for intoxication with PCP. 15.5 explain the mechanism of action, pharmacokinetics, and pharmacological actions of marijuana.
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Introduction
The widespread abuse of psychoactive drugs has become an unfortunate reality in today’s society. Whereas most drugs are used to alleviate disease and human suffering, a few drugs are abused for their mind-altering effects. Although they may provide pleasure, they are not solutions to life’s problems and can cause other health or social problems. Initially, the use of a psychoactive drug can provide the novelty of an experience that is often interpreted as pleasurable and exciting. After initial experimentation, many individuals realize the dangers of continued drug consumption and avoid further abuse. For other individuals, drug abuse appears to provide “the answer” for which they have been searching. With continued drug use, some individuals focus all of their attention and available resources on obtaining and consuming illicit drugs. They begin to feel that as long as they have the drug, nothing else really matters or is important. As drug abuse continues, drug tolerance develops and with some drugs larger doses must be consumed in order to attain previous drug effects. The euphoria and good feelings that were the reason for abusing the drug are no longer experienced. As drug dependency develops, consumption of larger doses may be necessary to prevent the onset of psychological and physical withdrawal symptoms, forming a vicious cycle from which it is difficult to escape without professional help and a major personal decision to avoid further drug abuse. This chapter examines the pharmacology of the psychotomimetic and related drugs of abuse. The abuse of narcotic analgesics, barbiturates, benzodiazepines, and alcohol is presented in other chapters. The psychotomimetic drugs of abuse have few therapeutic uses and do not form a distinct drug class. Psychoactive drugs of abuse can be divided into the lysergic acid diethylamide (LSD-type) hallucinogens; the psychomotor stimulants, which include the amphetamines, cocaine, and related designer drugs; and a miscellaneous group of drugs that includes phencyclidine (PCP) and marijuana.
LO 15.1 1
LO 15.2
LSD-TYPE HALLUCINOGENS Lysergic acid diethylamide (LSD) is a synthetic drug that was first prepared in 1938. It remains one of the most potent hallucinogenic drugs yet discovered. LSD and other hallucinogenic, or psychotomimetic, drugs produce similar pharmacological effects. At one time, LSD and other hallucinogenic drugs were investigated for the treatment of alcoholism and mental illness. Currently, these drugs have no therapeutic uses and are classified as Schedule I drugs under the Controlled Substances Act. The prototype of this group is LSD, and it will be discussed in greater detail.
Mechanism of Action How LSD produces its hallucinogenic effects is not exactly known. Evidence suggests that LSD and the other hallucinogens interact with serotonin receptors in the brain, primarily the 5HT2A receptors. The hallucinogens appear to have a mixed action referred to as partial agonism. A partial agonist binds to a receptor and weakly stimulates it. The drug (hallucinogen) 204
then remains on the receptor and acts as an antagonist to block the actions of the neurotransmitter, in this case serotonin. These actions disrupt normal brain activity and contribute to the sensory distortions and hallucinogenic effects.
Pharmacological Effects Lysergic acid diethylamide (LSD) is readily absorbed from the gastrointestinal tract. The average hallucinogenic dosage ranges from 50–100 mcg. The psychic effects of LSD usually last about 12 hours, with peak effects occurring 1 to 2 hours after oral administration. Common psychotomimetic effects include sensory distortions and pseudohallucinations. Moving objects appear to be followed by a stream of color or appear as vividly colored geometric patterns. Synesthesia may occur, where sensory perceptions are distorted and individuals perceive they are “seeing sounds” or hearing visual images. Perceptual distortions in the size of objects and parts of the body are common. Feelings of separation of part of the body, or loss of a part of the body, or failure to recognize a part as one’s own body also occur.
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Note to the Health Care Professional LSD and similar hallucinogens produce a sequence of dose-related effects that have been divided into three phases: • The somatic phase occurs initially after absorption, and it consists of CNS stimulation and autonomic changes that are predominantly sympathomimetic in nature. • The sensory phase is characterized by sensory distortions and pseudohallucinations (the user knows the hallucinations are not real), which are the effects desired by the drug user. • The psychic phase signals a maximum drug effect. Disruption of thought processes, depersonalization, and true hallucinations (the user believes the hallucinations are real) and psychotic episodes may occur. Experiencing this phase would be considered a “bad trip”.
In addition to the psychotomimetic effects, hallucinogenic drugs are potent stimulants of the central nervous system. Piloerection, pupillary dilation, and increased neuromuscular reflex activity can be observed. Cardiovascular effects include tachycardia and increased blood pressure. Lysergic acid diethylamide is also associated with the occurrence of flashbacks. A flashback, which can occur at any time after exposure to LSD, is characterized by many of the psychotomimetic effects of LSD without readministration of the drug. Flashbacks often occur after use of other psychoactive drugs, which somehow trigger flashback episodes.
Tolerance and Physical Dependency Tolerance develops rapidly to the psychotomimetic effects of LSD, usually within a few doses of continuous use. Also, cross-tolerance exists between LSD and the other drugs of this group, so subsequent doses of one drug taken shortly after another drug produce decreased effects. The tolerance is not accompanied by physical dependency, and abrupt discontinuance after chronic use does not precipitate withdrawal symptoms.
Intoxication and Treatment The signs and symptoms of LSD intoxication include elevated body temperature and blood pressure, tachycardia, hyperreflexia, dilated pupils, anxiety, hallucinations, and psychotic behavior. LSD has a high therapeutic
index, and virtually no known causes of death have been related to overdose toxicity by LSD alone. Consequently, treatment is aimed at protecting patients from accidental injury until the drug effects subside. Individuals should be placed in a quiet, nonthreatening environment and given reassurance that everything will be all right. Benzodiazepine antianxiety agents or barbiturates can be used for their sedative effects. This approach to treatment is considered standard therapy for most hallucinogenic drug intoxication.
Other LSD-Type Hallucinogens In addition to LSD, two other categories of drugs produce similar effects.
Tryptamine Derivatives Psilocybin and N,N-dimethyltryptamine (DMT) are obtained from natural sources. Psilocybin is found in the Psilocybe mushroom species, which have been eaten ceremonially by native cultures for centuries. Psilocybin is converted to an active metabolite, psilocin, which is believed to be responsible for the majority of psychotomimetic effects. The hallucinogenic dose of psilocybin is approximately 25 mg, which produces effects lasting 3 to 6 hours. N,N-dimethyltryptamine (DMT) occurs in many plants and has been used as a snuff by various Native American cultures. It is ineffective when taken orally; it must be inhaled or administered parenterally. The usual hallucinogenic dose given by injection is 1 mg per kg of body weight, which produces psychotomimetic effects lasting approximately 1 hour.
Phenethylamine Derivatives Mescaline and 2,-5-dimethoxy-4-methylamphetamine (DOM) are phenethylamine derivatives similar in structure to norepinephrine and amphetamine (Figure 15.1). Central nervous system stimulation and sympathomimetic effects are prominent features of both drugs. Mescaline, found in the peyote cactus, is among the least potent of the hallucinogenic drugs. It is readily absorbed from the gastrointestinal (GI) tract and produces effects that last about 6 hours. DOM, or STP (“Serenity, Tranquility, Peace”), is a synthetic compound. The usual hallucinogenic dose is 3–5 mg, which produces effects lasting 6 to 8 hours. LO 15.3
PSYCHOMOTOR STIMULANTS Amphetamine and cocaine are potent CNS stimulants that are widely used. At higher doses, these drugs produce prominent psychotomimetic effects. The central Chapter 15 • Psychotomimetic Drugs of Abuse
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Figure 15.1
Chemical Structure of the Adrenergic Neurotransmitter Norepinephrine I llustrating the Chemical Similarity to the Hallucinogens Mescaline and DOM, and to the Psychomotor Stimulant Amphetamine OH CHCH2NH2
HO
CH2CHNH2 CH3
HO Norepinephrine
Amphetamine
OCH3 CH3O
CH2CHNH2
CH2CH2NH2
CH3
CH3O
CH3 OCH3 Mescaline
OCH3 2,5-Dimethoxy-4-methylamphetamine
actions and pharmacological effects of these drugs are very similar. A number of drugs related to the amphetamines are known as “designer drugs.” A designer drug is a slightly altered derivative of an approved drug, such as amphetamines or narcotics. The effects are similar to those of the approved drug, but they are usually more intense and mind-altering. Designer drugs are synthesized by illegal laboratories and sold “on the street” for great profit. The major actions of amphetamines and cocaine occur within the brain. Both increase the amounts of norepinephrine (NE) and dopamine (DA) within the brain. The increased levels of NE produce prominent peripheral and central sympathomimetic effects. The higher levels of DA influence behavioral activity, particularly that involving the limbic system. The behavioral actions account for the ability of these drugs to act as potent reinforcers of behavior. This reinforcement acts to compel drug abusers to take the drug repeatedly.
Amphetamines A number of drugs are referred to as “amphetamines.” These include amphetamine itself, dextroamphetamine, methamphetamine (“speed”), and a few related drugs. The amphetamines are basically sympathomimetic amines with chemical structures very similar to NE and DA. There are, however, some important pharmacokinetic differences between the drugs and the neurotransmitters. 206
Pharmacokinetics In comparison to NE and DA, the amphetamines are lipid soluble and are not affected by the enzymes and inactivation mechanisms that quickly terminate the effects of the neurotransmitters. Consequently, the amphetamines are well absorbed orally, readily pass into the brain, and produce effects lasting several hours. Intravenous injection of amphetamines, especially methamphetamine (“speed”), has become a significant problem. Large amounts are often injected over several days, and during these sustained highdosage bouts, the psychotomimetic effects of the drug frequently occur.
Pharmacological Effects
Abuse of amphetamines is based on the action of these drugs to influence physical performance and psychological mood. After oral administration, people feel more confident, alert, talkative, and generally hyperactive. Amphetamines increase endurance and reduce feelings of fatigue. Following intravenous administration, users experience the initial “rush,” which has been described as orgasmic. The euphoria and excitement produced by amphetamines are important reinforcing properties on behavior. Compulsive behavior drives users to repeat the drug again and again in order to maintain the good feelings, the “reward.” After discontinuance of the drug, profound sleep usually occurs. Upon awakening, users experience disagreeable, depressed feelings (“crash”) and want to resume drug taking immediately. Initially, the hyperactivity may stimulate users to be more industrious and diligent, but eventually, performance deteriorates. Activity may continue for hours, but it may also become compulsive and highly stereotyped. Users get “hung up” doing one thing over and over again. As amphetamine usage increases and dosages become larger, the psychotomimetic effects become apparent and can lead to psychotic behavior. Amphetamine psychosis is similar to paranoid schizophrenia. Although users may feel elated, they appear glum, depressed, and withdrawn. Suspicion, hostility, and aggressive behavior may lead to violent acts. Sensory illusions, auditory and visual hallucinations, and distortions of body image may occur. Psychosis can occur after only a few doses, but it usually occurs after chronic use of high doses.
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Tolerance and Dependency Tolerance to amphetamines, especially after prolonged intravenous administration, develops rapidly, and larger amounts are usually administered with continuous use. Tolerance develops to the euphoria and to the appetite suppressant effect. Abrupt discontinuance of amphetamines after chronic use results in mild to moderate physical withdrawal symptoms. Withdrawal effects appear to be predominantly psychological in nature and include extreme fatigue, mental depression, and a strong desire for the drug.
Intoxication and Treatment A number of adverse effects and potential complications are caused by overstimulation of the sympathetic and central nervous systems. The psychotomimetic effects of the paranoid psychosis have already been described. Sympathetic stimulation produces hyperthermia and profuse sweating, respiratory difficulties, tremors, and various cardiovascular effects. Intense cardiovascular stimulation results in tachycardia, arrhythmias, and hypertension, which may contribute to intracranial hemorrhage and sudden death. After prolonged intravenous use, severe fatigue and exhaustion may be followed by convulsion, coma, and death. Chronic intoxication can produce all of these conditions, and, in addition, there may be extreme weight loss from lack of appetite. Treatment of amphetamine intoxication is aimed at supporting vital functions and providing symptomatic therapy. Acidifying the urine will increase excretion. Adrenergic blockers and vasodilators can be administered to control excessive sympathetic and cardiovascular stimulation. Diazepam is generally preferred to control seizures and also can be used for sedation when necessary. Highly agitated individuals can be given antipsychotic drugs, which reduce psychotic symptoms by antagonizing the actions of DA and NE.
Cocaine Cocaine was isolated from the leaves of Erythroxylon coca in 1855. Native Indians of South America have chewed coca leaves for centuries to ward off fatigue and hunger. In the late nineteenth century, cocaine was considered a “wonder drug” and advocated for treatment of numerous medical conditions, including morphine and alcohol addiction. After recognizing the potential dangers of cocaine abuse, the government enacted legislation in 1914 that restricted and controlled the use of cocaine. Cocaine was “rediscovered” in the 1970s when the phenomenon of recreational drug use dramatically increased. In recent years, the widespread abuse of cocaine has generated major social and medical problems.
The pharmacological effects of cocaine are similar to those of the amphetamines. However, cocaine possesses a number of features that make it more popular with drug users. Cocaine is prepared in different forms that can be administered by a variety of methods. The intensity and duration of drug effects are highly dependent on the preparation used and the route of administration.
Preparations of Cocaine Cocaine base is extracted from coca leaves and converted to a water-soluble hydrochloride salt. It is in this form that cocaine is exported and adulterated with other substances, such as sugars and local anesthetics. Cocaine hydrochloride can be administered orally, intranasally, and intravenously. It is destroyed, however, by the high temperatures generated during smoking. Several methods exist for conversion of cocaine hydrochloride back into free-base (without hydrochloride) form. Free-base cocaine possesses greater lipid solubility and a lower melting point. Consequently, it can be smoked, which allows almost instantaneous delivery of cocaine to the brain in a concentrated bolus. The intensity of effect is greatly increased. One form of free-base cocaine, “crack,” is prepared by an alkalinization-water process that forms a crystalline, rocklike substance that makes a cracking sound when it is smoked.
Pharmacokinetics Cocaine is absorbed from the intestinal tract and from all mucous membranes. Pharmacological effects are delayed (30 to 60 minutes) and are less intense after oral administration, compared to other routes. Drug effects are detectable 3 to 5 minutes after intranasal administration, peak in 20 to 30 minutes, and last 60 to 90 minutes. Plasma levels measured an hour or more after oral or intranasal administration are comparable; however, it is the concentration of cocaine in the brain that is important. Intranasal administration provides higher drug levels in the brain within a shorter period of time; therefore, the effects are more intense (Figure 15.2). Intravenous injection and smoking both provide immediate effects of high intensity but of shorter duration. Peak effects by these routes occur in minutes and last about 20 minutes. Smoking cocaine is the most popular route of administration; it is more convenient than making injections, and there is less nasal irritation (and no septal perforation) than when taken intranasally. The half-life of cocaine is about 30 to 40 minutes; the metabolites of cocaine are excreted in the urine.
Pharmacological Effects Cocaine is a powerful CNS stimulant, producing marked euphoria, self-confidence, and heightened feelings of Chapter 15 • Psychotomimetic Drugs of Abuse
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Figure 15.2 Man Inhaling Cocaine with a Glass Straw
degree of physical dependency. There is a mistaken perception by many that substances that only cause psychological dependency are generally safe. Cocaine is one of the most psychologically habituating drugs known, and individuals who become dependent on it suffer fates similar to those of individuals addicted to alcohol, narcotics, and other physically addicting drugs. The symptoms of withdrawal from cocaine include craving for the drug, dysphoria, irritability, anxiety, depression, tremors, eating and sleeping disturbances, and thoughts of suicide.
Intoxication and Treatment
physical and mental ability. These ego-reinforcing effects can lead to delusions of grandeur, which have been referred to as “cocainomania.” The positive psychological effects are followed by dysphoria, anxiety, and feelings of depression as the drug effect wears off, creating a desire in users to repeat the drug again, which often leads to prolonged binges where cocaine use becomes compulsive. This is similar to the situation that develops with amphetamines. However, the duration of action after smoking or injecting cocaine is only 20 to 30 minutes, compared to several hours with amphetamines. Consequently, cocaine must be administered much more frequently in order to maintain the good feelings. This frequency contributes to the reinforcing properties of cocaine on behavior and leads to drug dependency. As dosages of cocaine are increased, CNS stimulation becomes excessive. Tremors and myoclonic jerks develop and may progress to clonic-tonic convulsions. Peripheral sympathomimetic effects increase, and cardiovascular stimulation resulting in hypertension, tachycardia, and arrhythmias may progress to serious complications and sudden death. A toxic psychosis, similar to that caused by amphetamines, can develop after high dosages or prolonged use. Symptoms include hostility, social withdrawal, paranoia, hallucinations, delusions, and violent behavior.
Tolerance and Dependency The question of tolerance to cocaine is not entirely clear. Acute tolerance does develop to the sympathomimetic and psychological effects when cocaine is used frequently within short periods of time. Before widespread abuse in the 1970s, cocaine was considered a relatively safe drug that did not cause physical dependency. However, with the technique of free basing, where higher doses are administered frequently on a daily basis, the evidence suggests that cocaine does produce some 208
Depending on the dosage and time since administration, users may be euphoric and excited or dysphoric, anxious, and depressed. After prolonged binges of cocaine use, extreme fatigue, exhaustion, hyperthermia, seizures, and coma may occur. The most serious effects of acute cocaine poisoning are in the CNS and cardiovascular system, leading to convulsions and cardiac complications. Tachycardia and arrhythmias may precipitate ventricular fibrillation and sudden death. CNS stimulation is followed by severe CNS depression, resulting in respiratory failure and cardiovascular collapse. Individuals with underlying cardiovascular disease are at greater risks of complication and sudden death. The psychotic reactions that usually occur after prolonged use are similar to those observed with amphetamines. Treatment of cocaine intoxication is similar to that for amphetamine poisoning, supportive and symptomatic. Diazepam is useful to control seizures and for sedation. Since the half-life of cocaine is short, the greatest danger in acute intoxication occurs within the first few hours. Antipsychotic drugs such as chlorpromazine and haloperidol are useful because of their multiple effects to antagonize DA and NE. Treatment of cocaine dependency usually involves education of individuals to the dangers of continued use and behavioral modification to control compulsive desires for the drug. A newer approach to control cocaine dependency is the use of tricyclic antidepressants (TCAs). Treatment with TCAs has been reported to lessen the euphoric effects of cocaine and to reduce cravings for continued use of the drug.
Designer Drugs Several of the designer drugs are derivatives of the amphetamines. These include methylenedioxyamphetamine (MDA, or the “love drug”), methylenedioxymethamphetamine (MDMA, “Adam,” or “Ecstasy”), and methylenedioxyethamphetamine (MDEA, or “Eve”). These drugs are usually taken orally.
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Pharmacological Effects These amphetamine derivatives produce CNS stimulation, euphoria, and visual distortions. Larger doses produce anxiety, panic, excessive sympathetic stimulation, and paranoia. Chronic abuse often produces hallucinations and psychotic disturbances resembling schizophrenia.
Treatment Treatment of intoxication with these drugs is similar to that for amphetamines and cocaine. LO 15.4 4
LO 15.5
MISCELLANEOUS PSYCHOTOMIMETIC DRUGS Phencyclidine Phencyclidine (PCP, “angel dust”) was investigated for use as a general anesthetic in humans. However, because of a high incidence of emergence delirium, it was dropped from further consideration for this purpose. Phencyclidine is still used in veterinary practice to immobilize primates. Because of its psychotomimetic effects, the drug has gained wide popularity as a drug of abuse.
Mechanism of Action The pharmacology of PCP is complex. Phencyclidine produces multiple pharmacological actions, including CNS stimulation, CNS depression, peripheral autonomic effects, analgesia, and anticonvulsant activity. The psychotomimetic effect that occurs at nonanesthetic doses is varied and is the result of mixed CNS stimulant and depressant actions exerted at multiple brain sites. The main mechanism of action of PCP is antagonism of glutamate receptors that normally regulate certain ion channels. Glutamate is an excitatory amino acid and is associated with several different receptors. One of these receptors, the N-methyl-D-aspartate (NMDA) receptor, is blocked by PCP, resulting in the psychotomimetic effects.
Pharmacokinetics Phencyclidine can be administered by various routes, including inhalation (smoking), oral, insufflation (snorting), and intravenous injection. Like other anesthetics, PCP is lipid soluble and widely distributed to peripheral tissues, where it accumulates in fat, which accounts for the prolonged duration of action.
Pharmacological Effects The effects of PCP vary significantly with increasing dosage. At low doses, there is CNS stimulation, euphoria, and sympathetic stimulation similar to the effects produced by amphetamines. With increasing dosage,
thought processes become disoriented and speech is slurred. This is followed by paresthesia, slowed reflexes, and ataxia. Disorders of body image are common, with both elongation and shrinkage of extremities. This state may last 4 to 6 hours, after which a depressive state occurs, along with a paranoid behavior pattern. It may take several days before the affected individual returns to normal. In acute toxicity, individuals exhibit marked anxiety, agitation, hallucinations, and occasionally violent behavior. This may progress to dysphoria, catatonia, muscle rigidity, convulsions, nystagmus, hypertensive crisis, coma, and death.
Treatment of Intoxication Initial treatment is similar to that with LSD-type hallucinogens: a nonstimulating environment and reassurance. Propranolol to control excess sympathetic stimulation and diazepam for sedation may be administered when deemed necessary. Acidification of the urine to pH 5.5 will increase excretion of PCP and shorten the half-life.
Tolerance and Dependency Tolerance develops fairly rapidly to the behavioral and toxic effects of PCP during chronic use. PCP has been demonstrated to be a positive reinforcer of behavior. This indicates the development of some degree of dependency. The drug dependency appears to be predominantly psychological rather than physical. Withdrawal symptoms, when present, include a craving for the drug, increased anxiety, and mental depression.
Marijuana The source of marijuana is a species of hemp plant, Cannabis sativa (Figure 15.3). The flowering tops of the female plant are particularly rich in a sticky resin in which the psychoactive principals are found in the highest concentrations. The resin can be extracted from the plant and is known as hashish. Marijuana generally refers to the dried, chopped plant (seeds, flowers, twigs, leaves), which is smoked like tobacco. The pharmacologically active substances in marijuana are compounds referred to as cannabinoids. The major active cannabinoid present in the plant is tetrahydrocannabinol (THC). The resin, hashish, usually contains about 10 percent THC.
Pharmacokinetics The cannabinoids are highly lipid-soluble compounds. The most common route of administration of marijuana is smoking, which provides bioavailability of 10 to 25 percent, depending on the efficiency of smoking technique. Effects after smoking begin within 5 to 15 minutes, peak at 30 to 90 minutes, and generally last Chapter 15 • Psychotomimetic Drugs of Abuse
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Figure 15.3
may lead to a better understanding of the actions of the cannabinoids in the future.
Marijuana Leaves from Cannabis Sativa
Pharmacological Effects
3 to 4 hours. Tetrahydrocannabinol is widely distributed throughout the body, and the highly lipid-soluble THC is taken up by peripheral body compartments and sequestered in adipose tissue. Biotransformation of THC occurs predominantly in the liver by the microsomal enzyme system. Metabolic degradation is complex, with approximately 80 different metabolites already identified. The primary metabolite is active and equipotent with THC. This compound is subsequently biotransformed to a number of inactive metabolites, which are then eliminated, via the bile, into the feces, with the remainder excreted in the urine.
Mechanism of Action The mechanism of action of the cannabinoids is not well understood. However, a receptor has been identified in the brain that has been shown to bind cannabinoids. The receptor is referred to as the cannabinoid receptor (CB1). In addition, an endogenous substance, named anandamide, has been identified in the brain that is believed to bind to the cannabinoid receptor. This suggests that there may be cannabinoid-like substances that play some role in activities of the brain. These findings 210
Conjunctival reddening and increases in heart rate have been the most consistently reported effects of marijuana. Heart rate increases of 20 to 50 beats per minute may occur and are dose-related. Tolerance develops to this effect with chronic use. After one marijuana cigarette, the user usually experiences physical and mental relaxation, feelings of euphoria, and increased sociability. These feelings come and go as if in waves. Conversation and ideas tend to concentrate on the “here and now” and not on past or future circumstances. There is a sense that time is passing slowly. With moderate intoxication, there may be drowsiness, lapses of attention, and impairment of short-term memory. At high levels of intoxication, reflexes are slowed, muscle coordination decreases, ataxia is evident, and speech and the ability to concentrate become more difficult. Performance of a variety of tasks deteriorates. The more complex the task, the greater the degree of disruption produced. Dreamlike states with alterations of auditory and visual perceptions reflect the psychotomimetic actions of marijuana. Psychic effects also may include dysphoria, acute panicanxiety reactions, and psychotic episodes. Marijuana psychosis may, in part, be caused by unmasking of latent psychiatric disorders. It appears to occur under conditions of unusually heavy drug use. Symptoms are delirium, disorientation, and schizophrenic-like behavior. At low doses, marijuana produces a slight bronchodilation. However, marijuana smoke contains higher concentrations of tar and some carcinogens than does tobacco smoke. Chronic use can produce hoarseness, cough, and bronchitis. Heavy use results in increased airway resistance and has been associated with precancerous changes in the respiratory epithelium. Marijuana alters the plasma levels of some reproductive hormones. In males, lower testosterone levels decrease the sperm count and motility. In females, levels of luteinizing hormone (LH) and prolactin are suppressed, resulting in sporadic ovulation and irregular menstrual cycles. Tetrahydrocannabinol readily crosses the placenta, and teratogenic effects have been demonstrated in animal studies. Specific birth defects have not been observed in humans, but lower birth weights have been recorded in mothers who smoked marijuana during pregnancy. Experimental studies have shown marijuana to cause a mild, transitory immunosuppressant effect. Decreased levels of T-lymphocytes have been observed in some chronic users. The clinical significance of this effect has not been determined.
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Tolerance and Dependency
Intoxication and Treatment
Tolerance to marijuana—that is, diminished response to a given dose when repeated—has been demonstrated. However, the development of tolerance usually occurs only after prolonged use of higher amounts of marijuana. The tolerance is variable and develops to a greater degree for some effects, such as tachycardia, CNS depression, and euphoria. Tolerance is rapidly reversed after cessation of marijuana use. Some of the tolerance may be metabolic in origin and caused by induction of microsomal enzymes. As with chronic tobacco smoking, tars and residues in marijuana smoke stimulate the drug microsomal enzyme system. However, this effect on metabolism does not explain all of the tolerance that develops. Crosstolerance with other psychoactive drugs has not been demonstrated. Abrupt cessation of marijuana after prolonged use has indicated some dependency. The dependency appears to be more psychological than physical and of considerably less intensity than that observed with cocaine and amphetamines. Withdrawal symptoms are mild and not unlike those observed in individuals who quit the tobacco habit. Symptoms include dysphoria, anxiety, tremors, eating and sleeping disturbances, and increased sweating.
The most common intoxication reaction requiring treatment is acute panic-anxiety reaction, where users appear to lose control and feel as if they are losing their mind. This reaction occurs most frequently with inexperienced users, who are unfamiliar with the effects of marijuana. The effects rarely last more than a few hours. Diazepam may be administered to individuals who are particularly agitated. Psychotic reactions, which were discussed previously, occur after high doses or prolonged use and may require hospitalization and treatment with antipsychotic drugs.
Therapeutic Potential of THC Tetrahydrocannabinol and various derivatives have been investigated for treatment of nausea and vomiting, glaucoma, pain management, and other medical conditions. Dronabinol (Marinol), a drug formulation of THC, and nabilone (Cesamet), an analog of THC, are approved for use to combat the nausea and vomiting associated with chemotherapy. The capsules are administered several hours before and after administration of chemotherapy. Dronabinol also has been approved for the stimulation of appetite and prevention of weight loss in patients with a confirmed diagnosis of acquired immunodeficiency syndrome (AIDS). Dronabinol capsules are administered twice daily, before lunch and dinner.
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Chapter Review Understanding Terminology Match the definition or description in the left column with the appropriate term in the right column. (LO 15.1, 15.2, 15.3, 15.5) ___ 1. Because of this, doses of one drug taken shortly after another drug produce decreased effects.
a. cannabinoid
___ 2. Because of this, one consumes larger and larger doses of a drug in order to get the desired effects.
c. dependency
___ 3. Pharmacologically active substance found in the marijuana plant.
e. synesthesia
___ 4. Because of this, larger and larger doses of a drug are necessary to prevent withdrawal.
b. cross-tolerance
d. flashback
f. drug tolerance
___ 5. A distortion of sensory perception that occurs with the use of LSD. ___ 6. Hallucinogenic effect of LSD relived long after the use of LSD.
Acquiring Knowledge Answer the following questions. 1. Briefly describe the psychotomimetic syndrome. (LO 15.1) 2. List the pharmacological effects produced by LSD. What is synesthesia? (LO 15.1, 15.2) 3. Describe the development of tolerance to LSD. What does the term cross-tolerance refer to? (LO 15.1) 4. What is the usual treatment for LSD and other hallucinogenic drug intoxication? (LO 15.2) 5. What mechanism of action is common to both amphetamines and cocaine? (LO 15.3) 6. Characterize the development of tolerance and dependency with the psychomotor stimulants. (LO 15.3) 7. Describe the pharmacological effects produced by phencyclidine (PCP). (LO 15.4) 8. What do the terms marijuana, cannabinoid, tetrahydrocannabinol (THC), and hashish refer to? (LO 15.5) 9. List the common pharmacological effects produced by marijuana. (LO 15.5) 10. What adverse effects are associated with the chronic use of marijuana? (LO 15.5) Match the descriptions in the left column with the appropriate phase of hallucinogen use in the right column. (LO 15.1, 15.2) ___ 11. Produces the effects desired by the user.
a. psychic phase
___ 12. Occurs right after absorption of the hallucinogen.
b. sensory phase
___ 13. A “bad trip”.
c. somatic phase
___ 14. Consists of CNS stimulation and autonomic changes that are predominantly sympathomimetic in nature. ___ 15. Produces sensory distortions and pseudohallucinations. ___ 16. Characteristic of a maximum drug effect. ___ 17. Produces disruption of thought, depersonalization, hallucinations, and psychotic episodes.
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Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. Mark works in an emergency room (ER) that gets lots of illicit-drug-overdose cases. What treatment recommendations would be appropriate for the following patients? a. Patient A presents with LSD toxicity, experiencing anxiety, paranoia, and real hallucinations (as opposed to pseudohallucinations, which the individual knows are not real). (LO 15.2) b. Patient B presents with cocaine intoxication, following a prolonged binge on the drug. She has had a mild seizure and shows psychotic behavior, hyperthermia, and exhaustion. (LO 15.3) 2. Assume you work a drug abuse hotline. What aspect of drug abuse does each of the following callers exhibit? a. Caller A says he needs help quitting cocaine. His main reason for wanting to quit is that he can no longer afford to buy the amount of cocaine he needs to get high. He says it seems that he uses more every day, and he still doesn’t get as high as he did when he first started using the drug. (LO 15.3) b. Caller B says he thinks he needs to get medical help with his cocaine problem. He’s been using cocaine for months now, and he needs larger and larger doses just to keep from feeling sick and strung out. He can’t imagine going without the cocaine, but he knows things can’t go on this way, either. (LO 15.3) Questions 3–5 are designed for classroom discussion. 3. A coworker confides in you that working full time, going to school, and taking care of a child and husband are exhausting, so occasionally she takes amphetamines to help her get through it all. She doesn’t feel it is a problem because she only uses them when she needs to. What do you do? (LO 15.3) 4. You are over at a coworker’s house and she brings out some marijuana. What do you do? (LO 15.5) 5. A coworker suffers from chronic sinus problems. After many months, this coworker confides in you that she indulges in recreational use of cocaine. What do you do? (LO 15.3)
Multiple Choice Use your critical-thinking skills to answer the following questions. 1. Select the neurotransmitter receptor interaction that explains the mechanism of action of LSD and other hallucinogens. (LO 15.1) A. norepinephrine B. dopamine C. serotonin D. acetylcholine 2. LSD is associated with the following pharmacologic effects when taken repeatedly: (LO 15.2) A. rapid development of drug tolerance B. drug dependency and withdrawal symptoms C. cross-tolerance with other hallucinogens D. only A and C are true 3. Intravenous administration and abuse of psychomotor stimulants, such as methamphetamine, is associated with the following: (LO 15.3) A. increased sympathomimetic actions B. development of drug tolerance C. behavioral and psychotomimetic effects D. all statements are true
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Chapter Review Continued 4. The drug that possesses anesthetic properties and that acts by blocking glutamate receptors is (LO 15.4) A. cocaine B. methamphetamine C. phencyclidine D. MDMA 5. Select the statement(s) that are true concerning the use of marijuana. (LO 15.5) A. active ingredient referred to as THC B. believed to bind to a specific receptor in the brain C. frequent use associated with development of drug tolerance D. all statements are true
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Select all of the following procedures that apply to treatment of cocaine intoxication and dependency. (LO 15.3) A. antagonizing DA and NE B. placement in a quiet room C. behavior modification D. tricyclic antidepressants 2. Select the drugs that increase the levels of NE and DA. (LO 15.3) A. amphetamines B. lysergic acid diethylamide C. phencyclidine D. marijuana 3. What are the signs of PCP intoxication? (LO 15.4) A. hyperthermia B. hyperreflexia C. convulsions D. nystagmus 4. Which phases of dose-related effects include hallucinations? (LO 15.2) A. somatic phase B. sensory phase C. flashback phase D. psychic phase 5. Select the pharmacological effects of marijuana. (LO 15.5) A. disorders of body image B. increased heart rate C. mental relaxation D. conjunctival reddening
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Sequencing Place the following drugs in order of shortest duration of psychic effects to longest duration. (LO 15.1, 15.3, 15.4) _______________
_______________
_______________
_______________
Shortest
_______________ Longest
LSD DMT PCP STP psilocybin
Classification Place the following drugs into the appropriate category. (LO 15.1) MDEA
DOM
DMT
psilocybin
mescaline
MDMA
Tryptamine derivatives
Phenethylamine derivatives
Amphetamine derivatives
Documentation Based on the symptoms experienced by the patient upon arrival at the hospital, answer the following questions. (LO 15.1) Symptoms: Elevated body temperature Dilated pupils Seeing sounds Increased heart rate a. What psychotomimetic drug is the patient most likely intoxicated with? b. What additional symptoms could be experienced by this patient? c. If we were to administer a drug to help with this intoxication, which class of drugs would be most appropriate? d. What symptom would we be treating with the use of the above drug? e. What other treatments would be appropriate?
For interactive animations, videos, and assessment, visit:
www.mcgrawhillconnect.com Chapter 15 • Chapter Review
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Chapter 16
Antiepileptic Drugs DRUG CLASS AT A GLANCE
KEY TERMS
OTC
absence seizure: generalized seizure that does not involve motor convulsions; also referred to as petit mal.
NO
PRESCRIPTION YES SCHEDULED DRUGS
IV—barbiturates, benzodiazepines
FDA PREGNANCY CATEGORY
C, D— benzodiazepines, carbamazepine, phenytoin, valproic acid
INDICATIONS Treatment of epilepsy
anticonvulsant: drug usually administered IV that stops a convulsive seizure. antiepileptic drug: drug usually administered orally to prevent epileptic seizures. atonic seizure: generalized-type seizure characterized by a sudden loss of muscle tone. clonic: convulsive muscle contraction in which rigidity and relaxation alternate in rapid succession. convulsion: involuntary muscle contraction that is either tonic or clonic. epilepsy: CNS disorder characterized by uncontrolled nerve cell discharges and manifested by recurring, spontaneous seizures of any type. generalized seizure: seizure originating and involving both cerebral hemispheres that may be either convulsive or nonconvulsive. grand mal: older term for a generalized seizure characterized by full-body tonic and clonic motor convulsions. myoclonic: generalized seizures that are usually brief and often confined to one part of the body.
partial seizure: seizure originating in one area of the brain that may spread to other areas. seizure: abnormal discharge of brain neurons that causes alteration of behavior and/or motor activity. status epilepticus: continuous series of generalized tonic and clonic seizures, a medical emergency requiring immediate treatment. tonic: convulsive muscle contraction characterized by sustained muscular contractions. tonic-clonic: generalized seizure characterized by full-body tonic and clonic motor convulsions and loss of consciousness.
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Learning Outcomes
After studying this chapter, you should be able to 16.1 describe the main clinical features of generalized and partial epileptic seizures. 16.2 compare the mechanism of action and uses of phenobarbital with those of phenytoin, carbamazepine, and valproic acid.
16.4 identify the mechanism of action of ethosuximide and drugs used in the treatment of absence seizures. 16.5 describe the treatment of status epilepticus. 16.6 identify the preferred therapies for the different types of epileptic seizures.
16.3 identify the mechanism of action of the drugs primarily effective for partial seizures.
Introduction
A seizure is defined as an abnormal electrical discharge of brain neurons that results in alterations in behavior and/or involuntary movements. There can be many different causes of seizures including fever, metabolic disturbances, brain tumors, and drug toxicity. Epilepsy is a medical condition involving recurrent seizures that are caused by some underlying disturbance in the activity of neurons in the brain. The neuronal disturbance increases the excitability of neurons, which then discharge uncontrollably. The result is high-frequency repetitive firing of action potentials that cause an alteration of consciousness and that may be accompanied by some form of muscular twitching or convulsion. The characteristics and symptoms of the different types of seizures depend on the area of the brain that is experiencing the abnormal electrical discharge. Generalized seizures usually involve both hemispheres of the brain, while partial seizures are usually localized to specific areas. However, partial seizures can spread and become generalized. Successful treatment of epilepsy with antiepileptic drugs depends upon accurate neurological examination and identification of the type of seizure. There are a variety of antiepileptic drugs used to treat epilepsy. Some drugs are effective for multiple types of epileptic seizures, while other drugs are primarily indicated for a specific type of seizure.
LO 16.1
TYPES OF EPILEPSY There are different types of epilepsy, and proper diagnosis is essential to selection of proper treatment. An important diagnostic tool aiding in the detection of epilepsy is the electroencephalogram (EEG), which records the electrical activity of the brain. Specific types of epilepsy produce characteristic electrical patterns. These patterns can be readily recorded by the EEG and identified. Classification of the different epilepsies is based on a neurological examination and EEG evaluation. Epileptic seizures are classified as either generalized or partial.
Generalized Seizures Generalized seizures originate in and involve both cerebral hemispheres. They are classified as tonic, clonic,
tonic-clonic, myoclonic, atonic, and absence seizures.
Tonic-Clonic Seizures Tonic-clonic (grand mal) seizures are the most dramatic in appearance and involve loss of consciousness. They usually begin with tonic followed by clonic muscle contractions. The individual appears to jerk around due to the alternating muscle contractions and relaxations. Increases in blood pressure and heart rate, urination, defecation, and tongue biting are common. A seizure usually lasts several minutes. Following the seizure there is confusion, fatigue, and muscle soreness. A series of generalized seizures, particularly tonic-clonic, without cessation is referred to as status epilepticus. Status epilepticus is a major medical emergency and demands immediate treatment. Chapter 16 • Antiepileptic Drugs
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Myoclonic Seizures Myoclonic seizures produce muscle contractions that are usually brief and often confined to one part of the body; however, these seizures may spread and become generalized.
Atonic Seizures Atonic seizures involve a sudden loss of muscle tone. The individual usually falls and can suffer head and other bodily injuries.
Absence Seizures Absence seizures are generalized seizures that are usually confined to a brief impairment of consciousness. This may involve a form of staring into space or rapid eye blinking that lasts anywhere from a few seconds to less than a minute. Although there is impairment of consciousness, individuals usually do not fall or experience motor convulsions. After a seizure, activity often continues as if nothing had happened. There is usually a characteristic 3-second electrical spike wave that can be observed on the EEG. This type of epilepsy is also known as petit mal.
Partial Seizures Partial seizures are classified as either simple or complex.
Simple Partial Seizures Simple partial seizures may be sensory or motor in nature. These seizures usually involve a limited area of the brain and are often manifested by a sensory change (numbness) or muscular twitch that is confined to one body part. The seizures are brief in duration and usually there is no loss of consciousness.
Complex Partial Seizures Complex partial seizures involve impairment of consciousness, usually not longer than a minute or two, and are accompanied by some type of characteristic movement. These movements have been described as “purposeless” because they are not goal-directed and involve such things as lip smacking or other repetitive movements. Following the attack, the individual usually has no memory of what occurred during the seizure. Complex partial seizures may spread and include other areas of the body, or also may become tonic-clonic and involve the entire body. LO 16.2
DRUGS EFFECTIVE FOR BOTH GENERALIZED TONIC-CLONIC AND PARTIAL SEIZURES All of the primary drugs used to treat epilepsy possess anticonvulsant properties. An anticonvulsant is defined as a drug, usually administered IM or IV, that 218
terminates convulsive seizures. The term antiepileptic infers that the drug, usually administered orally, can be used prophylactically to reduce or prevent epileptic seizures. Not all drugs with anticonvulsant activity can be used in epilepsy; many anticonvulsant drugs produce a significant degree of sedation that interferes with performance of daily activities. Antiepileptic drugs decrease the excitability of brain cells and, consequently, reduce the incidence and severity of seizures. This action enables affected individuals to have greater control over their daily lives. Several different drug classes possess antiepileptic properties. Each of these will be discussed in relationship to the type of epilepsy for which it is used. The most frequently used antiepileptic drugs and their main indications are summarized in Table 16:1.
Barbiturates The barbiturates, previously discussed with respect to their sedative and hypnotic properties, are excellent anticonvulsant drugs. All barbiturates have anticonvulsant properties, but only a few, such as phenobarbital and mephobarbital, have the additional property of being antiepileptic. They have a selective effect at lower doses to prevent seizures. Sedation and hypnosis are common pharmacological effects produced by barbiturates. However, in the treatment of epilepsy, excessive sedation or hypnosis is an unwanted side effect. Fortunately, tolerance to the sedative and hypnotic effects develops with chronic use. The barbiturates are used alone or in combination with other antiepileptic drugs.
Mechanism of Action As previously discussed in Chapter 12, one of the actions of the barbiturates is to increase the inhibitory effects of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In the brain, this suppresses the excitability of epileptogenic neurons and makes them less likely to discharge and initiate a seizure. The effect on GABA occurs at lower doses and therefore limits the sedative and depressant effects of the barbiturates.
Clinical Indications Barbiturates, like phenobarbital, are currently used as alternatives to other more preferred drugs in the treatment of both generalized and partial seizures. Sudden discontinuation of barbiturates can produce convulsions. Therefore, when barbiturate withdrawal is desired, a patient’s dose should be gradually reduced over the course of 1 to 2 weeks. The pharmacology of the barbiturates can be reviewed in Chapter 12.
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Table 16:1
Antiepileptic Drugs Drug (Trade Name)
Primary mechanism of action
Dosage form
Drugs used for generalized tonic-clonic and partial seizures Carbamazepine (Tegretol )
Prolongs inactivation of Na+ channels
Tablets, capsules, suspension
Phenobarbital (Luminal )
Increases inhibitory actions of GABA
Tablets, elixir, IM, IV
Levetiracetam (Keppra)
Mechanism not clearly understood
Tablets, oral solution, IV
Phenytoin (Dilantin)
Prolongs inactivation of Na+ channels
Tablets, capsules, suspension, IV
Topiramate (Topamax)
Prolongs inactivation of Na+ channels
Tablets, capsules
Zonisamide (Zonegran)
Interference with Na+ and Ca++ channels
Capsules
Valproic acid (Depakene)
Prolongs inactivation of Na+ channels
Tablets, capsules, syrup, IV
Drugs effective primarily for partial seizures Felbamate (Felbatol )
Interference with Na+, Ca++, glutamate
Tablets, suspension
Gabapentin (Neurontin)
Blockade of Ca++ channels, decreased release of glutamate
Capsules, oral solution
Lacosamide (Vimpat)
Enhances slow inactivation of Na+ channels
Tablets, IV
Lamotrigine (Lamictal )
Prolongs inactivation of Na+ channels
Tablets
Pregabalin (Lyrica)
Same as gabapentin (above)
Capsules
Tiagabine (Gabitril )
Blocks neuronal reuptake of GABA
Tablets
Drugs effective for absence seizures Clonazepam (Klonopin)
Increases inhibitory actions of GABA
Tablets
Ethosuximide (Zarontin)
Inhibits thalamic T-type Ca++ currents
Capsules, syrup
Lamotrigine (Lamictal )
Prolongs inactivation of Na+ channels
Tablets
Trimethadione (Tridione)
Inhibits thalamic T-type Ca++currents
Chewable tablets, capsules
Valproic acid (Depakene)
Prolongs inactivation of Na+ channels
Capsules, syrup, IV
Drugs effective for status epilepticus Clonazepam (Klonopin)
Increases inhibitory actions of GABA
IM, IV
Diazepam (Valium)
Same as above
IM, IV
Lorazepam (Ativan)
Same as above
IM, IV
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Note to the Health Care Professional Follow the proper procedures for dispensing any controlled substances. Barbiturates and benzodiazepines are FDA Schedule IV controlled drugs. Warn patient never to suddenly stop taking medications unless advised by the physician as this may precipitate seizures. In the event a patient experiences a generalized seizure, be prepared to administer resuscitative measures.
Hydantoins The most important drug from this class is phenytoin (Dilantin). Phenytoin is a very potent antiepileptic drug, and it can be used in several types of epilepsy (Figure 16.1). It is one of the most important antiepileptic drugs available. A significant advantage of phenytoin is that it produces little sedation. Ethotoin (Peganone), mephenytoin (Mesantoin), and fosphenytoin (Cerebyx) are other hydantoins. Fosphenytoin is a more soluble prodrug of phenytoin that is administered by IM or IV injection.
Mechanism of Action The mechanism of action of phenytoin and the other hydantoins is complex and affects the activity of both neuron ion channels (Na+, K+, Ca++) and neurotransmitter functions. The primary effect of phenytoin is believed to prolong the inactivation period of sodium (Na+) channels in the nerve membrane. The result is a reduction in generation of the high-frequency repetitive firing of action
potentials from neurons involved in initiating seizures. Figure 16.2 compares some normal EEG brain waves with those recorded during an epileptic seizure.
Clinical Indications Phenytoin is used for all types of partial seizures and for tonic-clonic generalized seizures. It also can be administered IV in acute situations to arrest convulsive seizures including the treatment of status epilepticus.
Adverse Effects The adverse effects of the individual hydantoins are similar. The most common adverse effects involve the cerebellum. The symptoms are dizziness, ataxia, visual disturbances, and postural imbalance. Other adverse effects include skin rashes, hirsutism, and gingival hyperplasia. Good dental hygiene may prevent the overgrowth of the gums. Phenytoin has been associated with birth defects referred to as the “fetal hydantoin syndrome.” Defects include craniofacial abnormalities, growth retardation, cardiac defects, learning and developmental problems, and limb defects. It is listed as FDA Pregnancy Category D.
Carbamazepine (Tegretol ) Carbamazepine is structurally related to the tricyclic antidepressants. The mechanism of action is similar to that of phenytoin and involves an action to prolong the Figure 16.2 Comparison of Normal Brain Waves with the High-Frequency Repetitive Firing of Action Potentials Observed During an Epileptic Seizure Beta (β) 13–30 Hz awake, alert, eyes open
Figure 16.1 Drug Label for Phenytoin ( Dilantin )
Alpha (α) 8–13 Hz awake, relaxed, eyes closed
EEG waves
Theta (θ) 4 – 8 Hz
Delta (δ) 0.5 – 4 Hz Epilepsy spiking
Phenytoin is one of the most important antiepileptic drugs available that is effective for both generalized and partial seizures, and the treatment of status epilepticus.
220
0
1 Time (s)
2
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inactivation of Na+ channels. This decreases the neuronal influx of sodium ions and inhibits high-frequency and repetitive firing of neurons.
effective for treatment of partial seizures. Valproic acid is also effective in the treatment of bipolar disorder.
Clinical Indications
The most common side effects of valproic acid are nausea, vomiting, diarrhea, and tremor. The most serious problem with valproic acid has been the development of a potentially fatal liver toxicity, especially in young patients. The cause of the liver toxicity has been linked to the metabolites of valproic acid, which are hepatotoxic. Valproic acid has been associated with birth defects such as spina bifida and both facial and digital abnormalities. The FDA has listed this drug as Pregnancy Category D.
Adverse Effects
Carbamazepine is used in the treatment of all types of partial seizures and generalized tonic-clonic seizures. It also is indicated for the treatment of mania and bipolar disorder (Chapter 14). Carbamazepine possesses analgesic properties and also is indicated for treatment of trigeminal neuralgia.
Adverse Effects Common side effects include nausea, vomiting, diplopia, drowsiness, and dizziness. More serious effects involve liver disturbances, jaundice, and bone marrow depression, which may lead to aplastic anemia. In overdosage, carbamazepine may cause convulsions and respiratory depression. Carbamazepine is listed as FDA Pregnancy Category D and has been associated with spina bifida, craniofacial defects, and developmental delay.
Primidone (Mysoline) Primidone is chemically related to the barbiturates. Most of the drug is metabolized and converted in the body into phenobarbital, which is believed to account for most of its antiepileptic effects. Primidone is effective against both generalized and partial seizures but is primarily an alternate choice to drugs such as carbamazepine, phenytoin, and valproic acid. Common adverse effects include sedation and gastrointestinal disturbances; other adverse effects are similar to those of phenobarbital.
Valproic Acid (Depakene) Valproic acid is one of the few drugs that can be used in all types of epilepsy. Like carbamazepine and phenytoin, valproic acid decreases the influx of Na+ ions and inhibits high-frequency firing of neurons (Figure 16.3). In addition, valproic acid blocks excitatory glutamate (NMDA) receptors and increases the inhibitor effects of GABA. These multiple actions are most likely the reason for its effectiveness in almost all types of epilepsy. Valproic acid administered alone produces very little sedation.
Levetiracetam (Keppra ) The mechanism of action of levetiracetam is poorly understood. The main indication is as adjunctive therapy in the treatment of partial seizures in adults and the treatment of generalized tonic-clonic seizures in children. The drug may be taken without regard to meals and significant drug interactions have not been reported. The most frequently reported adverse effects include sleepiness, dizziness, headache, tiredness, and nervousness.
Clinical Indications Valproic acid is very effective against absence seizures and generalized tonic-clonic seizures. In addition, it is Figure 16.3
The Effect of Several Antiseizure Drugs on Voltage-Induced, Sustained, HighFrequency Firing of Neuronal Action Potentials Phenytoin
Carbamazepine
Sodium valproate
Time
Time
Time
Time
Voltage
Control
On
Off
On
Off
On
Off
On
Off
When compared to the control recording, phenytoin, carbamazepine, and sodium valproate markedly reduce the number of voltage-induced action potentials.
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Topiramate (Topamax ) The actions of topiramate are not clearly understood but are believed to interfere with the action of Na+ ions and generation of high-frequency action potentials. The drug also may increase the inhibitory actions of GABA. Topiramate is indicated for therapy of both tonic-clonic and partial seizures. The drug is absorbed well, is excreted mostly unchanged, and does not appear to cause significant drug interactions. Adverse effects include sleepiness, dizziness, tiredness, mental confusion, and, less frequently, formation of renal stones. Studies have demonstrated teratogenic effects in animals and it is classified as FDA Pregnancy Category C.
Zonisamide (Zonegran ) The mechanism of action of zonisamide involves interference with both Na+ and Ca++ ion channel activity to inhibit the high-frequency firing of neurons. Indications are for generalized tonic-clonic and partial seizures; it also has shown activity against some myoclonic seizures. Zonisamide is well tolerated. Adverse effects involve minor CNS disturbances, sleepiness, rashes, and occasional development of renal stones. LO 16.3
DRUGS EFFECTIVE PRIMARILY FOR PARTIAL SEIZURES Felbamate (Felbatol ) Felbamate is indicated for the treatment of partial seizures. Mechanisms of action include interference with sodium (Na+) ions, blockade of calcium (Ca++) channels, and blockade of glutamate receptors. Unfortunately, felbamate has been associated with the development of aplastic anemia and liver failure. Consequently, the drug is reserved for patients who do not respond to other drugs and whose epilepsy is so severe that the benefits of therapy outweigh the risks of developing these serious adverse effects.
Gabapentin (Neurontin), Pregabalin (Lyrica ) Gabapentin is similar in structure to GABA and was designed to act in a similar manner. However, the major antiepileptic actions are believed to involve blockade of Ca++ ion channels and decreased release of the excitatory neurotransmitter glutamate. Gabapentin is primarily used in patients over 12 years of age in combination with other antiepileptic drugs in the treatment of partial seizures. The most common adverse effects include sleepiness, headache, dizziness, ataxia, tremor, and tiredness. 222
Pregabalin is also related to GABA and similar to gabapentin in pharmacologic properties. It is indicated for adjunctive therapy of partial seizures. In addition, it is approved for treatment of neuralgia (nerve pain) and related conditions such as fibromyalgia.
Lacosamide (Vimpat ) Lacosamide is a newer drug that is indicated for add-on therapy with other drugs in the treatment of partial seizures in patients age 17 or older. The mechanism of action of lacosamide is believed to involve enhancement of the slow inactivation of voltage-sensitive Na+ channels, which inhibits the repetitive firing of neurons. Common adverse effects include blurred vision, headache, dizziness, and ataxia. Hypersensitivity reactions and disturbances of the electrical activity of the heart also may occur.
Lamotrigine (Lamictal ) The mechanism of action of lamotrigine includes inactivation of Na+ ion channels to decrease high-frequency firing of neurons and inhibition of Ca++ ion channels. The drug is used alone and in combination with other antiepileptic drugs in the treatment of partial seizures. Lamotrigine also has demonstrated activity against absence, myoclonic, and atonic seizures. In addition, it is one of the antiseizure drugs indicated for treatment of bipolar disorder. The most common adverse effects include dizziness, ataxia, sleepiness, headache, visual disturbances, and allergic rash. The rash usually develops during the first few weeks of treatment and in some cases has progressed to Stevens-Johnson syndrome, a severe type of dermatitis that can be life-threatening.
Tiagabine (Gabitril ) Tiagabine is believed to block the neuronal reuptake of the inhibitory transmitter GABA back into its nerve endings. This increases synaptic GABA levels that are now available for receptor stimulation. The drug is indicated for the treatment of partial seizures alone or in combination with other drugs. Common adverse effects include nausea, GI disturbances, abdominal pain, dizziness, tremors, nervousness, and mental confusion. LO 16.4
DRUGS USED IN THE TREATMENT OF ABSENCE SEIZURES Succinimides The succinimides are a group of compounds that are only used in the treatment of absence seizures. The most important and most widely used succinimide is ethosuximide (Zarontin). Ethosuximide has a long half-life
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that usually allows twice-a-day dosing. The mechanism of action is related to the ability of ethosuximide to decrease specific calcium currents (T-type currents) in the thalamus. These calcium currents are believed to play an important role in causing absence seizures. The succinimides commonly produce GI disturbances such as nausea, vomiting, and diarrhea. In addition, some drowsiness and dizziness may occur. Less frequently there may be decreases in white blood cells and platelets. In addition to ethosuximide, lamotrigine and valproic acid (both previously discussed) are the drugs most frequently used for treatment of absence seizures.
Oxazolidinediones The oxazolidinediones are another class of drugs indicated for absence seizures. The main drug of this class is trimethadione (Tridione). The mechanism of action is similar to that of ethosuximide, reduction of T-type calcium (Ca++) currents. The oxazolidinediones are considerably more toxic than the succinimides. One of the adverse effects characteristic of the oxazolidinediones is hemeralopia, or “snow blindness,” a visual disturbance in which patients seem to be looking at everything as if through a snowfall. Hypersensitivity reactions such as rashes and blood disorders usually necessitate alternate therapy. In addition, cases of liver and kidney damage have been reported. Trimethadione is rarely prescribed today because of the higher incidence of adverse effects and toxicities.
Benzodiazepines As discussed in Chapter 13, the benzodiazepines possess anticonvulsant activity. These drugs act by increasing the inhibitory effects of GABA. Diazepam (Valium), clonazepam (Klonopin), and lorazepam (Ativan) are the drugs used as anticonvulsants. Diazepam and lorazepam are usually administered intravenously to stop seizures that are in progress, usually tonic-clonic seizures, and for the treatment of status epilepticus (see below). Clonazepam also is used as an antiepileptic drug in the treatment of myoclonic and akinetic seizures, and in cases of absence seizure unresponsive to ethosuximide or other drugs. The main side effect of these drugs in the treatment of seizures is sedation. The adverse effects of the benzodiazepines were presented in Chapter 13.
order to prevent severe CNS, cardiovascular, and respiratory depression. Lorazepam is currently considered the drug of choice to treat status epilepticus. Diazepam (Figure 16.4) is equally effective but has a shorter duration of action when administered IV and may require additional administration. Parenteral administration of fosphenytoin or phenytoin is also effective for treatment of status epilepticus. Once status epilepticus is under control, other antiepileptic drugs used in the chronic treatment of epilepsy can be administered orally to prevent further seizures. LO 16.6
PREFERRED THERAPY FOR EPILEPTIC SEIZURES There are a large number of antiepileptic drugs and the choice of treatment often depends on the age, seizure type, and individual patient characteristics.
Generalized Tonic-Clonic Seizures Phenytoin (Dilantin) is usually considered the drug of choice. Valproic acid (Depakene) and carbamazepine (Tegretol ) are also first-line drugs. Lamotrigine (Lamictal ) and topiramate (Topamax) are also effective and particularly useful in children because of the lower incidence of adverse effects.
Partial Seizures There are a number of drugs that are equally effective for partial seizures. Phenytoin (Dilantin), carbamazepine (Tegretol ), and valproic acid (Depakene) are usually the preferred drugs. Newer drugs such as lamotrigine (Lamictal ) and topiramate (Topamax) are also effective and serve as alternate therapy. Figure 16.4 Drug Label for Diazepam
LO 16.5
TREATMENT OF STATUS EPILEPTICUS Status epilepticus is a medical emergency where a series of seizures occur without interruption. Tonic-clonic-type seizures, in particular, require immediate treatment in
IV administration of diazepam is considered to be one of the drugs of choice for the treatment of status epilepticus.
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Patient Administration and Monitoring Monitor vital signs when anticonvulsant drugs are administered intravenously, especially when treating seizures in progress.
Explain to patient the importance of taking drugs as prescribed and the dangers of missing doses since this may precipitate seizures.
Explain to patient the common side effects of most drugs: nausea, dizziness, ataxia, and sedation.
Instruct patients to report seizures and other significant adverse effects.
Caution patients about the dangers of engaging in hazardous activities, such as driving while under the influence of drugs.
Instruct patients not to take other drugs unless they check with their physician or pharmacist.
Instruct patients to take medications with meals if nausea or GI disturbances are excessive, especially with carbamazepine, ethosuximide, and phenytoin.
Absence Seizures Ethosuximide (Zarontin) has usually been the drug of choice for these seizures, especially in children. Valproic acid (Depakene) and lamotrigine (Lamictal ) are also effective drugs and may be preferred in adults, especially when other seizure types are also present.
Status Epilepticus The drug of choice to arrest status epilepticus is now considered to be lorazepam (Ativan) administered IV. Diazepam is equally effective but has a shorter duration of action when administered IV and may require additional administrations. Depending on the situation, administration of lorazepam may be followed with IV administration of phenytoin (Dilantin) or fosphenytoin (Cerebyx).
Antiepileptic Drug Interactions There are a variety of drug interactions involving the antiepileptic drugs. When used in combination, these
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drugs often produce drug interactions with each other. Carbamazepine, phenobarbital, and phenytoin cause microsomal enzyme induction and increase the rate of metabolism of any other drug requiring microsomal metabolism. This results in reduced drug effects and duration of action of the drugs requiring metabolism. Valproic acid inhibits the microsomal enzymes and will therefore increase the effects of drugs requiring microsomal metabolism. Cimetidine (Tagamet) and other drugs that inhibit microsomal enzymes will increase the concentrations and effects of anticonvulsant drugs requiring microsomal metabolism, especially carbamazepine. Some antiepileptic drugs, such as phenytoin and valproic acid, are highly plasma protein bound. They can displace and be displaced by other drugs that are also highly protein bound. This increases the free drug concentration (unbound fraction) of the drug displaced and produces greater pharmacologic effects.
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Chapter Review Understanding Terminology Match the definition or description in the left column with the appropriate term in the right column. (LO 16.1) ___ 1. Drug that prevents or stops a convulsive seizure.
a. anticonvulsant
___ 2. Drug that prevents epileptic seizures.
b. antiepileptic
___ 3. Condition characterized by periodic seizures or convulsions.
c. epilepsy
___ 4. Generalized seizure only involving a brief impairment of consciousness.
d. generalized seizure (grand mal)
___ 5. Seizures characterized by full-body tonic and clonic convulsions.
f. complex partial seizure
___ 6. Continuous series of generalized seizures.
g. status epilepticus
e. absence seizure
___ 7. Seizure characterized by some purposeless body movement or sensory change.
Acquiring Knowledge Answer the following questions. 1. Describe what occurs to the brain cells in epilepsy. (LO 16.2, 16.3) 2. List the common types of epilepsy and describe the characteristics of each. (LO 16.1) 3. In what types of epilepsy is phenytoin most useful? (LO 16.2) 4. What is the mechanism of action of phenytoin (Dilantin)? (LO 16.2) 5. List the adverse effects of phenytoin. (LO 16.2) 6. What drugs are used primarily to treat absence seizures? (LO 16.4) 7. List the adverse effects of trimethadione (Tridione). (LO 16.4) 8. What is the drug of choice for treating status epilepticus? (LO 16.5)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. Assume that you assist with medications in a busy neurological practice and you’ve been asked to deal with each of the following cases. a. Patient A is a 14-year-old female who frequently has short periods when she loses consciousness. After each seizure, she continues what she was doing as though nothing happened. How would you characterize the type of epilepsy this patient has? (LO 16.4) b. Patient B has absence epilepsy. What drug is usually considered the preferred therapy? (LO 16.4, 16.6) c. How would you advise Patient C about adverse effects for the antiepileptic drug trimethadione? (LO 16.4) d. Patient D has tonic-clonic convulsions in progress. What should be done? (LO 16.5) 2. Freddy suffers from absence seizures. Zarontin has not adequately controlled them. His physician has decided to add a benzodiazepine to his drug therapy. Which one would be appropriate? (LO 16.4) 3. What are the additional clinical indications for carbamazepine other than epilepsy? (LO 16.2)
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Chapter Review Continued Multiple Choice Use your critical-thinking skills to answer the following questions. 1. The type of seizure characterized by sustained muscle spasms is (LO 16.1) A. absence B. clonic C. tonic D. simple partial 2. The preferred drug for treatment of absence seizures is (LO 16.4) A. primidone B. ethosuximide C. phenobarbital D. trimethadione 3. Hirsutism, gingival hyperplasia, and rash are adverse effects associated with (LO 16.2) A. valproic acid B. carbamazepine C. lamotrigine D. phenytoin 4. The drug of choice for treatment of status epilepticus is (LO 16.5) A. fosphenytoin B. phenobarbital C. lorazepam D. valproic acid 5. Fetal hydantoin syndrome is associated with (LO 16.2) A. diazepam B. topiramate C. ethosuximide D. phenytoin 6. Carbamazepine, phenytoin, and valproic acid all share a common mechanism of action to (LO 16.2) A. decrease the release of GABA B. prolong inactivation of Na+ channels C. increase T-type calcium currents D. increase influx of Ca++ ions
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Select the main symptoms of a generalized seizure. (LO 16.1) A. numbness B. muscle twitch in the arm C. loss of consciousness D. purposeless movement
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2. What are the mechanisms of action of phenobarbital? (LO 16.2) A. increase inhibitory effects of GABA B. prolong inactivation of sodium channels C. block excitatory glutamate receptors D. decrease neuronal influx of Na+ 3. Which of the following are mechanisms of action for drugs used for partial seizures? (LO 16.3) A. inhibit Ca++ channels B. block neuronal reuptake of GABA C. interfere with sodium ions D. decrease release of glutamate 4. Which drugs would be considered in the treatment of status epilepticus? (LO 16.5) A. felbamate B. lorazepam C. levetiracetam D. phenobarbital 5. Select all of the drugs used in the treatment of absence seizures. (LO 16.4) A. Zarontin B. Tridione C. Paradione D. Valium
Classification Place each drug under the type of seizure for which it is the preferred treatment. (LO 16.6) Dilantin Zarontin Ativan Valium Neurontin Keppra Felbatol Tridione
Generalized tonic-clonic
Partial seizures
Absence seizures
Status epilepticus
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Chapter Review Continued Documentation Using the label provided, answer the following questions.
a. What different type of seizures can be treated with this medication? b. What is the mechanism of action for this medication? c. If our patient cannot swallow capsules, are there other dosage forms available? What are they?
Labeling
Voltage
Fill in the missing labels. (LO 16.2)
Time On
Time Off
On
Time Off
On
Time Off
On
Off
For interactive animations, videos, and assessment, visit:
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Chapter 17
Antiparkinson Drugs DRUG CLASS AT A GLANCE
KEY TERMS acetylcholine (ACH): excitatory neurotransmitter in the basal ganglia.
OTC
NO
PRESCRIPTION
YES
SCHEDULED DRUGS
NO
basal ganglia: group of cell bodies located within the cerebrum involved in regulation of skeletal muscle tone and body movement.
FDA PREGNANCY CATEGORY
B, C
bradykinesia: slowed body movements.
INDICATIONS Parkinson’s disease, parkinsonism
dopamine: inhibitory neurotransmitter in the basal ganglia. dyskinesia: abnormal involuntary body movements. dystonia: muscle spasms, facial grimacing, and other involuntary movements and postures. on-off phenomenon: alternating periods of movement mobility and immobility. parkinsonism: symptoms of Parkinson’s disease, which include resting tremor, muscle rigidity, and disturbances of movement and postural balance. Parkinson’s disease: movement disorder of the basal ganglia caused by a deficiency of dopamine. rigidity: a stiffness and inflexibility of movement. tremor: a trembling and involuntary rhythmic movement.
Learning Outcomes
After studying this chapter, you should be able to 17.1 list the major symptoms of Parkinson’s disease. 17.2 explain the relationship between dopamine and acetylcholine in the basal ganglia. 17.3 explain the mechanism of action of levodopa and understand the common adverse effects and different movement disorders that occur over time with this drug.
17.4 identify the mechanism of action of the MAO-B and COMT inhibitors and how they affect levodopa metabolism. 17.5 list the dopamine receptor agonist drugs and explain their mechanism of action and adverse effects. 17.6 explain the therapeutic role of amantadine and the anticholinergic drugs.
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Introduction
The basal ganglia are a group of cell bodies (gray matter) located within the white matter of the cerebrum. The major function of the basal ganglia is to help regulate skeletal muscle tone and body movement. The most common disease involving the basal ganglia is Parkinson’s disease. Parkinson’s disease is caused by degeneration of neurons in the substantia nigra (one of the basal ganglia) that produce dopamine (DA). The deficiency of DA is the main cause of the symptoms and progression of Parkinson’s disease. Some antipsychotic drugs (Chapter 13) that block DA receptors also can cause symptoms of Parkinson’s disease; this is referred to as parkinsonism. The reason for degeneration of the dopaminergic neurons in Parkinson’s disease is not known. However, with aging there is a gradual loss of DA neurons. Environmental factors, genetic predisposition, and destruction by free radicals are a few of the factors that have been linked to the increased destruction of DA neurons. In individuals who develop Parkinson’s disease there appears to be an accelerated loss of DA neurons. Parkinson’s disease is treated primarily by drug therapy. Although drug treatment is effective in reducing the symptoms of the disease, the disease continues to progress because of the continued destruction of the neurons that produce dopamine. Individuals may eventually become physically disabled, wheelchair bound, and bedridden in the later stages of the disease. In addition to the movement disturbances, there are also a variety of other symptoms. These include hypotension, increased sweating, salivary drooling, and urinary and intestinal disturbances. Also, patients may experience mental depression, anxiety, and other behavioral changes. Several different classes of drugs are used to treat Parkinson’s disease. The main therapeutic aim is to administer drugs that increase the activity and concentration of dopamine in the basal ganglia.
LO 17.1 1
LO 17.2
NEUROTRANSMITTERS AFFECTING THE BASAL GANGLIA Normal function of the basal ganglia depends mainly upon the interaction between two neurotransmitters: acetylcholine (ACH) and dopamine (DA). ACH and DA help regulate the activity of the motor nerves that control voluntary muscle movements. ACH is an excitatory neurotransmitter released by neurons from one of the basal ganglia known as the corpus striatum. ACH increases muscle tone and activity. DA is an inhibitory neurotransmitter released by neurons from another of the basal ganglia, known as the substantia nigra. DA inhibits muscle tone and activity. Parkinson’s disease is caused by destruction of the DA neurons in the substantia nigra. The location of the corpus striatum, substantia nigra, and other basal ganglia within the cerebrum can be seen in Figure 17.1. Normally, the activity of ACH and that of dopamine are balanced, allowing smooth and well-controlled body movements. The deficiency of dopamine in Parkinson’s disease disturbs the balance between ACH and dopamine in favor of ACH. The increased activity of ACH produces excessive motor nerve stimulation, resulting in tremors, muscle rigidity, bradykinesia, and the other symptoms of Parkinson’s disease. 230
The earliest symptoms of Parkinson’s disease are usually tremor and muscular rigidity, followed by bradykinesia. The tremors are referred to as “resting tremors” because they only occur when the patient is not moving. Often the initial symptoms appear only on one side of the body but eventually affect both sides. As the disease progresses, the ability to maintain normal posture and balance is affected and the patient may fall. In late-stage disease, the patient may be physically disabled, wheelchair bound, or bedridden. Figure 17.2 summarizes the clinical features, symptoms, and approach to management of an individual with Parkinson’s disease. Several different classes of drugs are used to treat Parkinson’s disease and are classified according to their mechanisms of action ( Table 17:1). LO 17.3
LEVODOPA ( DOPAR, LARODOPA ) In Parkinson’s disease, there is a deficiency of dopamine in the basal ganglia. When administered as a drug, dopamine does not readily cross the blood-brain barrier to enter the brain. However, the precursor of dopamine, l-dihydroxyphenylalanine (levodopa or L-DOPA), does cross the blood-brain barrier into the brain. Levodopa is
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Figure 17.1
Coronal Brain Section through the Forebrain Showing the Position of the Striatum, Substantia Nigra, and Related Structures
VL nucleus of thalamus
Basal ganglia and associated structures: Caudate nucleus Putamen
Striatum
External segment of globus pallidus Internal segment globus pallidus Subthalamic nucleus Substantia nigra
Figure 17.2
Summary of the Clinical Features, Symptoms, and Nursing Management Approach for a Patient with Parkinson’s Disease
Nursing management Medication therapy as prescribed Rehabilitation Client and family education
Clinical features Head bent forward Tremors of the head Masklike facial expression Drooling
Warm baths and massage to relax muscles Instruction about medication therapy Bowel routine Self-help devices to meet daily needs: Raised toilet seat Long-handled comb Exercise to loosen joint structures
Rigidity Stooped posture Weight loss Akinesia (absence or poverty of normal movement) Resting tremor Loss of postural reflexes Bone demineralization
Range-of-motion exercises to prevent deformities
Shuffling and propulsive gait
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Table 17:1
Antiparkinson Drugs Drug (Trade Name)
Mechanism of action
Drugs that form dopamine Levodopa (Dopar, Larodopa)
Converted to dopamine in basal ganglia
Levodopa/carbidopa (Sinemet)
Same as above plus inhibition of peripheral conversion of l-dopa to DA, more l-dopa enters brain
Drugs that inhibit metabolism of levodopa or DA Carbidopa (Lodosyn)
Inhibits peripheral conversion of l-dopa to dopamine
Selegiline (Eldepryl )
Inhibits MAO-B to increase DA levels in the brain
Rasagiline (Azilect)
Inhibits MAO-B to increase DA levels in the brain
Tolcapone (Tasmar)
Inhibits COMT in the periphery and brain
Entacapone (Comtan)
Inhibits COMT in the periphery
Dopamine receptor agonist Bromocriptine (Parlodel )
Directly stimulates DA receptors in basal ganglia
Pramipexole (Mirapex)
Same as above
Ropinirole (Requip)
Same as above
Miscellaneous drugs Amantadine (Symmetrel )
Increases concentrations of DA in the brain
Anticholinergic drugs benztropine (Cogentin), others
Decrease excessive cholinergic activity in basal ganglia
structurally similar to the amino acid phenylalanine and is transported through the blood-brain barrier by the amino acid transporter that normally transports amino acids into the brain. In the dopaminergic neurons of the substantia nigra, levodopa is converted to dopamine. As the level of dopamine increases, there is lessening of parkinsonian symptoms and a significant improvement in physical mobility. Many patients are able to resume normal physical activities. Although not all patients respond to levodopa, it is the most effective drug available.
Pharmacokinetics Levodopa is administered orally and is well absorbed from the GI tract. The plasma half-life varies between 1 and 3 232
hours. Levodopa is usually administered on an empty stomach since the amino acids in foodstuffs can interfere with the transport of levodopa across the blood-brain barrier. A large amount of the levodopa given is rapidly converted to dopamine before passing into the brain and basal ganglia. In order to minimize this premature conversion, levodopa is usually given along with another drug, carbidopa. Carbidopa (Lodosyn) inhibits the enzyme that converts levodopa to dopamine so that more levodopa passes into the brain before being converted to dopamine. Carbidopa does not cross the blood-brain barrier and, therefore, does not prevent the conversion of levodopa to dopamine in the basal ganglia. When administered alone without carbidopa, levodopa is mostly metabolized
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Figure 17.3
Estimation of the Percentage of Levodopa That Reaches the Brain When Administered Alone (1–3%) versus the Percentage That Reaches the Brain When Administered with Carbidopa (10%) Levodopa alone 100%
Levodopa dose
30%
1–3%
Blood Gut
Brain
70%
27–29%
Metabolism in the Gl tract
Peripheral tissues (toxicity)
Levodopa with carbidopa 100% Levodopa dose
80%
10%
Blood Gut Brain 40%
50%
Metabolism in the Gl tract
in the GI tract and only 1–3 percent of the drug enters the brain. When carbidopa is added, which is standard therapy, the amount of levodopa entering the brain rises
Peripheral tissues (toxicity)
to about 10 percent (Figure 17.3). The addition of carbidopa also allows the dosage of levodopa to be reduced, which lowers the incidence of adverse effects. Chapter 17 • Antiparkinson Drugs
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A combination of levodopa and carbidopa is available under the trade name of Sinemet, and is the most widely used drug preparation. There are several different preparations of Sinemet that provide different ratios of carbidopa and levodopa. Sinemet 10–100 has 10 mg of carbidopa and 100 mg of levodopa. There are also Sinemet 25–100, Sinemet 25–250, and Sinemet CR (controlled release tablets) 25–100 and 50–200. A drug trial period often determines the proper patient dosage.
Adverse Effects The most common adverse effects of levodopa are nausea, vomiting, and loss of appetite (anorexia). In the brain, high levels of dopamine interfere with cardiovascular reflexes that maintain blood pressure. Consequently, some patients experience orthostatic hypotension or fainting. Since dopamine can stimulate beta-1-adrenergic receptors (Chapter 6), some patients may experience rapid or irregular heartbeat, especially if large amounts of levodopa are converted to dopamine in the peripheral circulation. Increased formation of dopamine in the limbic system and thalamus also may cause various behavioral and psychotic-like disturbances. Adverse drug reactions related to movement disorders are common as treatment with levodopa continues. Usually motor complications begin within one year and gradually progress over time. One of the movement disorders occurs as a drug dosage wears off. This is referred to as the end-of-dose wearing-off effect, which causes immobility. Dyskinesias and dystonias can occur at different times but particularly when drug concentrations in the basal ganglia are at their highest levels (peak). These involuntary movements frequently involve the head and neck. The patient also may experience periods of sustained contractions and become “frozen” in one position. Another effect that may occur as drug treatment progresses is the on-off phenomenon. This is characterized by alternating periods of mobility and immobility during drug therapy. The on-off phenomenon is not well understood but is believed to involve fluctuating levels of dopamine in the basal ganglia. Smaller doses taken at more frequent intervals appears to help. In addition, patients are usually instructed not to take their drug doses at or around meal time, especially if the meal contains large amounts of protein. The amino acids in protein can compete with and decrease the amounts of levodopa that are transported through the blood-brain barrier into the brain.
Drug Interactions A number of drugs interfere with the action of levodopa. The antipsychotic drugs (phenothiazines, haloperidol, drugs that block DA) decrease the effectiveness of 234
levodopa because they block dopamine receptors. This may cause symptoms of Parkinson’s disease, referred to as parkinsonism. MAO-A inhibitors used in treating mental depression also should not be taken with levodopa. They can produce high levels of norepinephrine and may cause a hypertensive crisis and other adverse effects. Vitamin B6, or pyridoxine, may increase the rate of metabolism of levodopa if the patient is not also taking carbidopa. When used as a vitamin supplement, vitamin B6 may decrease the effectiveness of levodopa. LO 17.4
ENZYME INHIBITORS THAT INCREASE THE ACTIONS OF LEVODOPA There are three different types of enzyme inhibitors that are used to increase the formation of dopamine in the brain and prolong the duration of dopamine once it is formed in the brain. Carbidopa (previously discussed) inhibits DOPA decarboxylase to increase the amount of levodopa that enters the brain. Drugs that inhibit the enzymes monoamine oxidase-B (MAO_B) and catecholO-methyltransferase (COMT) also inhibit the metabolism of levodopa and dopamine to prolong the duration of action of dopamine in the brain (Figure 17.4).
Monoamine Oxidase-B Selegiline (Eldepryl) Selegiline is a drug that primarily inhibits the metabolism of dopamine in the brain. Dopamine is metabolized by the enzyme monoamine oxidase-B (MAO-B). By inhibiting MAO-B, selegiline increases the concentration and prolongs the duration of action of the dopamine that is formed in the brain. The drug has been administered alone early in Parkinson’s disease in an attempt to slow progression of the disease but results are inconclusive. The drug is more commonly used in combination with levodopa to increase and prolong the effects of dopamine. The usual dosage is 5 mg taken at both breakfast and lunch.
Rasagiline (Azilect) Rasagiline is also an MAO-B inhibitor that is more potent then selegiline and considered more effective. There is some evidence that rasagiline may slow the progression of Parkinson’s disease when used early in the disease. The usual daily dose is 0.5–1 mg. Adverse effects of selegiline and rasagiline are associated with increased dopamine levels and are similar to those of treatment with levodopa, but occur with less frequency and intensity. At very high doses these drugs also can inhibit monoamine oxidase-A (MAO-A). MAO-A is
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the enzyme that primarily metabolizes norepinephrine, epinephrine, and serotonin. Serious drug interactions may occur when selegiline or rasagiline is administered together with either the MAO-A inhibitors or the selective serotonin reuptake inhibitors (SSRIs) used to treat mental depression (Chapter 14).
Catechol-OMethyltransferase C at e c h ol- O -met hylt r a n s fe r a s e (COMT) is another enzyme that normally is involved in the metabolism of dopamine both peripherally and in the brain. Drugs such as tolcapone (Tasmar) and entacapone (Comtan) inhibit COMT in the periphery and increase the amounts of levodopa that reach the brain. Tolcapone also inhibits COMT in the brain. These drugs are administered with levodopa to increase drug levels and prolong the duration of action of dopamine. A triple combination of levodopa, carbidopa, and entacapone is available under the trade name of Stalevo; this combination reduces the number of pills that a patient must take each day. Adverse effects caused by these drugs are due mostly to increased levodopa and dopamine levels and include nausea, orthostatic hypotension, mental disturbances, and dyskinesias. Tolcapone also can increase liver enzymes, hepatic toxicity, and possible hepatic failure. Use of tolcapone requires a signed patient consent and periodic monitoring of liver function.
Figure 17.4
Inhibition of the Metabolism of Levodopa (L-DOPA) and Dopamine by Drugs That Inhibit Monoamine Oxidase-B (MAO-B), CatecholO-Methyltransferase (COMT), and DOPA Decarboxylase Pramipexole, ropinirole, bromocriptine, and pergolide stimulate dopamine receptors
Dopamine receptors
Selegiline and rasagiline inhibit MAO-B
Tolcapone inhibits COMT
MAO MAO O-B B DOPAC AC (in nactiv ve meta aboli a olites es))
Dopamine
COM CO COM MT 3-O 3 OMD
DOPA decarboxylase Brain
Blood-brain barrier L-amino acid transporter
Periphery 3-O 3 3-O -OM MD D
L-DOPA COM COM MT
Entacapone and tolcapone inhibit COMT
Dop Do Dop opam ami mine min DOPA D DOP DO OPA decarb dec decarb arbo oxyl oxy ox o xy ylas las lase ase e
Carbidopa inhibits DOPA decarboxylase
Adverse effects
Carbidopa inhibits DOPA decarboxylase, while entacapone and tolcapone inhibit COMT to allow more L-DOPA to enter the brain. Tolcapone also inhibits COMT in the brain. Selegiline and rasagiline inhibit MAO-B to slow the metabolism of dopamine in the brain. Bromocriptine, pramipexole, and ropinirole are dopamine agonists that stimulate dopamine receptors. O-methyldopa (OMD) and dihydroxyphenylacetic acid (DOPAC) are inactive metabolites of L-DOPA and dopamine.
LO 17.5
DOPAMINE RECEPTOR AGONISTS Dopamine receptor agonists are drugs that enter the brain and bind to and stimulate dopamine receptors in the basal ganglia. These drugs act like levodopa but have longer durations of action. They can be used alone early in treatment or in combination with levodopa as Parkinson’s disease progresses. Compared to levodopa, these drugs cause a lower incidence of movement disturbances
and dyskinesias. Also, when used with levodopa, there is usually less incidence of the on-off phenomenon and other motor disturbances caused by levodopa. Bromocriptine (Parlodel ) was the first DA agonist used in Parkinson’s disease and it produces a variety of other pharmacologic effects. In addition to stimulating DA receptors, bromocriptine also stimulates alphaadrenergic and serotonin receptors, which can cause additional side effects. It is less effective than newer drugs and therefore rarely used today. Chapter 17 • Antiparkinson Drugs
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Newer dopamine receptor agonists pramipexole (Mirapex) and ropinirole (Requip) have become the preferred DA receptor agonists. These drugs can be used alone early in Parkinson’s disease or in combination with levodopa as the disease progresses and requires greater drug therapy. Pramipexole and ropinirole are usually administered three times per day; however, ropinirole is also available as extended release tablets (Requip XL), which requires only once-a-day administration. Adverse effects are similar to levodopa and include nausea, vomiting, postural hypotension, dizziness, and CNS disturbances that include sleepiness, delusions, hallucinations, and related psychotic effects. The DA receptor agonists are claimed to cause less movement disturbances but more mental disturbances than levodopa. Most of these effects are related to excess stimulation of dopamine receptors. Apomorphine (Apokyn) is another DA receptor agonist that is administered subcutaneously when patients are experiencing the off periods of the on-off phenomenon. Often these patients may be stuck or “frozen” in one position for extended periods of time. Use of this drug requires the supervision of a physician. LO 17.6
MISCELLANEOUS DRUGS Amantadine (Symmetrel ) Amantadine is an antiviral drug that was accidentally discovered to be beneficial in treating Parkinson’s disease. The drug is usually indicated during the early stages of Parkinson’s disease and often becomes ineffective after a few months of treatment.
Mechanism of Action
the drug is stopped. The discoloration is referred to as livedo reticularis.
Anticholinergic Drugs Over a century ago, it was observed that anticholinergic drugs such as atropine and scopolamine relieved some of the symptoms of Parkinson’s disease. Before the discovery of levodopa, anticholinergic drugs were the main treatment for parkinsonism. When there is a deficiency of dopamine in the basal ganglia, there is excess ACH (cholinergic) activity. By blocking ACH actions, the anticholinergic drugs decrease the level of cholinergic activity. The main therapeutic effects of anticholinergic drugs are to reduce the symptoms of tremor and muscular rigidity. Atropine and scopolamine produce a high incidence of peripheral anticholinergic side effects. The anticholinergic drugs that act primarily in the brain and that produce a lower incidence of peripheral side and adverse effects are the drugs used. These include benztropine (Cogentin), trihexphenidyl (Artane), and others. The anticholinergic drugs are listed in Table 17:2.
Clinical Indications Anticholinergic drugs are less effective than levodopa and the dopamine agonists. In some patients, the combination of levodopa and an anticholinergic drug provides improved results. Anticholinergic drugs also are used in patients treated with antipsychotic drugs who develop parkinsonism. By blocking cholinergic receptors in the basal ganglia, these drugs lower the effects of acetylcholine and help restore the acetylcholine/dopamine balance that is important for normal basal ganglia function. The basic pharmacology of the anticholinergic drugs was previously discussed with the parasympathetic nervous system in Chapter 7. It might be helpful to review this information at this time.
The mechanism of action of amantadine is unclear but believed to involve increased neuronal release of DA and decreased reuptake of DA back into the nerve Table 17:2 endings. Both actions increase the amount of DA available to stimulate DA receptors. Anticholinergic Amantadine, in oral doses of 100 to 200 mg per day, appears to work best when it is used in Disease the early stages of the disease and in combinaDrug (Trade Name) tion with other antiparkinson drugs.
Adverse Effects The main adverse effects of amantadine are dry mouth, gastrointestinal (GI) disturbances, and a number of CNS effects, usually visual disturbances, dizziness, and confusion. In addition, some patients experience a peculiar type of skin discoloration that clears up when 236
Drugs Used in Parkinson’s Common daily oral dosage range
Benztropine (Cogentin)
0.5–4 mg
Biperiden (Akineton)
6–10 mg
Procyclidine (Kemadrin)
7.5–15 mg
Trihexyphenidyl (Artane)
1–10 mg
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Patient Administration and Monitoring Measure vital signs when possible to detect decreases in blood pressure or increases in heart rate caused by drugs that act through dopamine.
with urination. Remember that these drugs are used with caution in patients with glaucoma, those with prostate hypertrophy, and the elderly.
Instruct patients on the importance of following dosing schedules and that missed doses will result in movement difficulties and an increase in parkinsonian symptoms.
Warn patients about the end-of-dose effect and the on-off phenomenon that may occur, and to report these occurrences since adjustments in dosage or diet may be helpful.
Explain to patient the expected side effects of drugs that increase dopamine activity: nausea, dizziness, sleepiness, and occasionally CNS disturbances such as vivid dreams or hallucinations.
Warn patients to be extremely careful when engaged in activities where impairment or temporary loss of movement could endanger their safety.
Explain to patient the side effects of anticholinergic drugs: dry mouth, constipation, visual disturbances, difficulties
Adverse Effects The main adverse effects associated with anticholinergic drugs are caused by a decrease in parasympathetic activity. They include dry mouth, constipation, urinary retention, rapid heartbeat, and pupillary dilation (mydriasis). LO 17.3 3
LO 17.4 4
LO 17.5 5
LO 17.6
PREFERRED THERAPY FOR PARKINSON’S DISEASE The most effective drug for treatment of Parkinson’s disease is the combination of levodopa and carbidopa. However, because of the movement disorders that occur with levodopa over time, levodopa therapy is often delayed in favor of other drugs until symptoms require more effective medications. Age is also a factor; older patients over 65 are often started with levodopa, while younger patients are often started with other drugs.
Treatment of Tremor as Predominant Symptom In early stages of parkinsonism, tremor and rigidity may be the only symptoms. Often one of the anticholinergic
drugs or amantadine may control these symptoms. In addition, rasagiline (MAO-B inhibitor) also may be considered. Initial treatment with these drugs allows the use of the more potent and effective drugs to be postponed until they are required to treat the more severe symptoms of the disease.
Treatment of Mild-Moderate Disease As initial symptoms of tremor, rigidity, and bradykinesia worsen, either one of the dopamine receptor agonists or levodopa/carbidopa are added to treatment. Low doses of these drugs are initiated and increased until symptoms are controlled. COMT and MAO-B inhibitors also may be added to levodopa to increase brain drug levels and duration of action.
Treatment of Advanced Disease In advanced disease increased dosages and more frequent administrations of levodopa/carbidopa are usually required. COMT and MAO-B inhibitors are added if not already prescribed. Dopamine receptor agonists also can be added to the treatment. The severity of disease and patient response often determine which drugs are prescribed.
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Chapter Review Understanding Terminology Answer the following questions. ___ 1. How are the terms parkinsonism and Parkinson’s disease related? (LO 17.1) ___ 2. Define the terms dyskinesia and dystonia. (LO 17.3)
Acquiring Knowledge Answer the following questions. 1. What two neurotransmitters normally control the activity of the basal ganglia? What happens in Parkinson’s disease? (LO 17.2) 2. Describe the main symptoms of Parkinson’s disease. (LO 17.1) 3. What is the mechanism of action of levodopa? Carbidopa? Selegiline? (LO 17.3, 17.4) 4. List the adverse effects associated with levodopa. (LO 17.3) 5. What drug interactions are possible with levodopa therapy? (LO 17.3) 6. Why are anticholinergic drugs useful in the treatment of Parkinson’s disease? (LO 17.6) 7. What side effects are produced by anticholinergic drugs? (LO 17.6) 8. What is the mechanism of action of amantadine (Symmetrel)? (LO 17.6) 9. Describe the mechanism of pramipexole (Mirapex). (LO 17.5)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. The local university hospital has a neurological clinic that treats many patients with Parkinson’s disease. Why might each of the following patients treated this week at the clinic be prescribed a drug other than Sinemet? a. Patient A has been taking Sinemet for 2 weeks and complains of fainting when getting out of bed, a racing heart, and loss of appetite. (LO 17.3) b. Patient B is a self-confessed “health nut” who takes multiple vitamin supplements every day, including all of the B vitamins. (LO 17.3) c. Patient C is taking Marplan for depression. (LO 17.4) 2. Why might each of the following patients be prescribed a drug other than Artane? a. Patient A has been taking Artane for a week and presents with nausea, constipation, rapid heartbeat, and fever. (LO 17.6) b. Patient B is taking haloperidol for Tourette’s syndrome. (LO 17.4) 3. Explain why the combination product Sinemet is so commonly used in treating Parkinson’s disease. (LO 17.3) 4. How do you think taking the combination tablet Sinemet would increase patient compliance over taking Dopar and Lodosyn separately? (LO 17.3)
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Multiple Choice Use your critical-thinking skills to answer the following questions. 1. Symptoms of Parkinson’s disease would be increased by (LO 17.1) A. excess levels of acetylcholine B. treatment with some antipsychotic drugs C. decreased levels of dopamine D. all statements are true 2. The drug classified as a dopamine receptor agonist is (LO 17.5) A. amantadine (Symmetrel) B. benztropine (Cogentin) C. ropinirole (Requip) D. entacapone (Comtan) 3. Select the drugs that increase the duration of action and/or the amount of levodopa that enters the brain. (LO 17.3, 17.4) A. carbidopa (Lodosyn) B. tolcapone (Tasmar) C. selegiline (Eldepryl) D. all statements are true 4. In Parkinson’s disease, slowed movements are defined as (LO 17.1, 17.2) A. rigidity B. bradykinesia C. tremor D. dystonia 5. Sinemet is the trade name of a drug combination that contains (LO 17.3) A. levodopa, carbidopa, and entacapone B. levodopa and entacapone C. levodopa and carbidopa D. levodopa and selegiline 6. The COMT inhibitor that has been associated with causing liver toxicity is (LO 17.4) A. ropinirole (Requip) B. entacapone (Comtan) C. pramipexole (Mirapex) D. tolcapone (Tasmar)
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Select the symptoms of Parkinson’s disease. (LO 17.1) A. hypertension B. decreased sweating C. salivary drooling D. movement disturbances
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Chapter Review Continued 2. Choose the correct statements about acetylcholine and dopamine. (LO 17.2) A. DA inhibits muscle activity B. ACH and DA are normally balanced C. ACH is an inhibitory neurotransmitter D. DA increases muscle tone 3. Which of the following drugs would be used to decrease ACH? (LO 17.6) A. amantadine B. levodopa C. bromocriptine D. procyclidine 4. Select the mechanisms by which levodopa works. (LO 17.3) A. crosses blood-brain barrier by an amino acid transporter B. converted to dopamine in the neurons C. increases level of dopamine D. inhibits monoamine oxidase B 5. Select the actions of Parlodel. (LO 17.5) A. stimulates DA receptors B. inhibits alpha-adrenergic receptors C. inhibits decarboxylase D. stimulates serotonin receptors
Sequencing Place the following mechanisms of action for levodopa in order of the first step to the last. (LO 17.3) –––––––––––––––––
–––––––––––––––––
–––––––––––––––––
First
––––––––––––––––– Last
levels of dopamine increase crosses blood-brain barrier converted to dopamine lessening of parkinsonism symptoms
Classification Put each drug under the correct mechanism of action. (LO 17.3, 17.4, 17.5) entacapone pramipexole
rasagiline
selegiline
tolcapone
Inhibit MAO-B
240
ropinirole
Inhibit COMT
Stimulate DA receptors
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Matching Match the following drugs with their correct classifications; each classification may be used more than once (LO 17.4, 17.5) a. dopamine receptor agonists b. monoamine oxidase inhibitors c. catechol-O-methyltransferase inhibitors 1. 2. 3. 4. 5. 6. 7.
_____ _____ _____ _____ _____ _____ _____
Mirapex Eldepryl Tasmar Comtan Parlodel Azilect Requip
Documentation Using the prescription below, answer the following questions. (LO 17.5)
Falls Clinic Practice RX 1000 River Avenue Anytown, USA 12345 931-555-1000 NAME:
Bob Jones
DATE:
ADDRESS: RX
Mirapex 0.25mg
Sig:
1 tablet once daily
Dr L. Hayden Substitution Permitted DEA #:
#30
M.D.
M.D. Dispense as written REFILL:
NR
1
2
3
4
a. What is the drug classification for this particular drug? b. What is the mechanism of action of this drug? c. What other medications in this class could be used for once-a-day dosing?
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Chapter Review Continued Labeling Fill in the missing labels. (LO 17.4)
Pramipexole, ropinirole, bromocriptine, and pergolide stimulate dopamine receptors
Selegiline and rasagiline inhibit MAO-B
Tolcapone inhibits COMT
MAO MAO O-B B
COM CO COM MT
DOPAC AC (in nactiv ve meta abol ab a olites es))
3 OM 3-O MD
DOPA decarboxylase Brain
Blood-brain barrier L-amino acid transporter
Periphery 3-O 3 3-O -OM MD D
COM COM MT
Entacapone and tolcapone inhibit COMT
DOPA D OPA decarb de d dec ec ecarb arb arbo a rbo rbo oxyl ox oxy xy ylas lase lase ase
Carbidopa inhibits DOPA decarboxylase
Adverse effects
For interactive animations, videos, and assessment, visit:
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Chapter 18
General Anesthetics DRUG CLASS AT A GLANCE
KEY TERMS adipose tissue: tissue containing fat cells.
OTC
NO
PRESCRIPTION YES
akathesia: continuous body movement in which an individual is restless or constantly paces about.
SCHEDULED DRUGS
YES
akinesia: loss of voluntary muscle movement; restless leg movement.
FDA PREGNANCY CATEGORY
B, C, D barbiturates CIII, CIV, fentanyl CII, midazolam CIV
INDICATIONS Anesthesia induction or maintenance, MAC Sedation, Supplement other anesthetics
analgesia: decreased response to pain; condition in which painful stimuli are not consciously interpreted (perceived) as hurting. cation: positively charged ion. dehiscence: busting open or separation of a wound, usually along sutured line. dissociative anesthesia: form of general anesthesia in which patients do not appear to be unconscious. dyskinesia: uncontrollable, involuntary repetitive movements, spastic. emetogenic: a substance that causes vomiting. euphoria: feeling of well-being or elation; feeling good. expectorate: eject from the mouth; spit. extrapyramidal syndrome: movement disorders such as akathisia, dystonia, and parkinsonism caused by antipsychotic drug therapy.
general anesthesia: deep state of unconsciousness in which there is no response to stimuli, including painful stimuli. halogenated hydrocarbon: compound that contains halogen (chlorine, fluorine, bromine, iodine) combined with hydrogen and carbon. hyperpolarized: a change in the cell membrane potential that makes the inside of the cell even more negative, so it can't respond to stimulation. hyperthermia: abnormally high body temperature. hypothalamus: center of the brain that influences mood, motivation, and the perception of pain. hypoxia: reduction of oxygen supply to tissues below the amount required for normal physiological function. induction of general anesthesia: time required to take a patient from consciousness to Stage III of anesthesia.
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maintenance of general anesthesia: ability to keep a patient safely in Stage III of anesthesia. medullary depression: inhibition of automatic responses controlled by the medulla, such as breathing or cardiac function. medullary paralysis: condition in which overdose of anesthetic shuts down cardiovascular and respiratory centers in the medulla, causing death. microcilia: tiny hairs that line the respiratory tract and continuously move, pushing secretions toward the mouth. neuroleptanalgesia: condition in which a patient is quiet and calm and has no response to pain after the combined administration of an opioid analgesic (fentanyl) and a tranquilizer (droperidol). neuroleptanesthesia: state of unconsciousness plus neuroleptanalgesia produced by the combined administration of nitrous oxide, fentanyl, and droperidol. neurotransmitter-gated ion channel: receptor-ion complex in the membrane that opens and allows rapid transmission of signal. preferred anesthetic: produces adequate anesthesia with minimal side effects. prodrug: an inactive precursor of a drug, converted into its active form in the body by normal metabolic processes. synergism: when the action resulting from a combination of drugs is greater than the sum of their individual drug effects. therapeutic dose: dose at which the desired effect is produced.
Learning Outcomes
After studying this chapter, you should be able to 18.1 identify the various stages of general anesthesia with the physical responses as the central nervous system (CNS) is depressed and define balanced anesthesia and monitored anesthesia care. 18.2 name two classes of general anesthetics by their routes of drug administration and describe the physiological effects associated with their use. 18.3 explain how anesthetics modulate CNS neuronal conduction.
18.5 describe how volatile liquid anesthetics are excreted from the body and how this differs from the way local anesthetics are excreted. 18.6 explain what an adjunct to anesthesia is and cite two examples of drug adjuncts used with general anesthetics. 18.7 list three side effects and contraindications that may be associated with anesthetic use. 18.8 list the preferred uses of anesthetics.
Mild inhibition of cortical activity reduces anxiety, whereas more intense depression of the lim-
Introduction 244
18.4 explain why more than one anesthetic may be administered to provide muscle relaxation without totally depressing the brain.
bic and reticular systems produces sleep. Sleep is a state of unconsciousness in which stimulation such as yelling or shaking will arouse an individual. General anesthesia is a deeper state of unconsciousness (sleep), in which an individual cannot respond to stimulation. During general anesthesia, all sensations are inhibited. Because sensations are suppressed, general anesthesia is used primarily to prevent the reactions to painful stimuli associated with surgery.
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LO 18.1 1
LO 18.2
Note to the Health Care Professional
GENERAL ANESTHESIA Drugs discussed in the previous chapters selectively depress the central nervous system (CNS). General anesthesia agents are a diverse group of drugs that abolish pain by modulating the function of the CNS at various sites. The extent of CNS depression under general anesthesia is much greater than that produced by other CNS depressant drugs (tranquilizers, sedatives, and hypnotics) at therapeutic doses. All of the major areas of the CNS are suppressed except for the medullary centers that regulate the vital organs (heart and lungs). An anesthesiologist controls the delicate balance between the beneficial effects of anesthesia and medullary depression, which can result in medullary paralysis and death.
Signs and Stages of Anesthesia General anesthesia is produced by gradually depressing the CNS. The sequence of depression is divided into four stages, as illustrated in Figure 18.1. During Stage I, the cerebral cortex is gradually inhibited. This stage is characterized by a decreased response to pain (analgesia), a
Figure 18.1
Because the anesthetics used today move quickly from Stage I to Stage III, most patients will not exhibit signs of the excitation phase. Occasionally this phase may be observed in children during induction and emergence from anesthesia when mask induction anesthesia is used. Being aware of this keeps the observer alert to potential safety issues in the recovery period.
feeling of euphoria (well-being or elation), and a loss of consciousness (sleep). Once the cerebral cortex is fully depressed, Stage II is achieved and the hypothalamus assumes control of body functions. Stage II is known as the “excitement phase” because there is an overall increase in sympathetic tone. Blood pressure, heart rate, respiration, and muscle tone increase during this stage. During Stage II, cardiac arrhythmias may occur. Eventually, respiration becomes
Signs and Stages of Anesthesia with CNS Depression
Euphoria, giddiness, loss of pain, loss of consciousness
Stage I Analgesia
Cerebral cortex
Stage II Excitement (delirium)
Sleep, normal blood pressure and respiration
Stage III Surgical anesthesia
Dilated pupils, loss of corneal reflex
plane 1 plane 2 plane 3
Hypothalamus Thalamus
plane 4 Stage IV Medullary paralysis
Increased sympathetic tone: elevated blood pressure and heart rate, hyperreaction to stimulation
Medulla Oblongata
Skeletal muscle relaxation Paralysis of the diaphragm, hypotension Respiratory paralysis leads to circulatory collapse and death
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more regular as excitation is inhibited. This change in respiratory pattern is an indication that patients are in Stage III. Stage III is usually referred to as surgical anesthesia because surgery is most efficiently performed at this level of general anesthesia. Stage III is divided into four planes (1–4) that reflect the progressive depth of CNS depression. During this stage, cardiovascular and respiratory functions return to normal, spinal reflexes are inhibited, and skeletal muscles are relaxed. Surgical incisions can be made throughout Stage III without producing pain or skeletal muscle contraction. Stage IV is the phase of medullary paralysis. This stage represents an overdose of general anesthetic, in which cardiovascular and respiratory centers in the medulla are inhibited and death occurs. The clinical signs associated with each stage of general anesthesia vary with the general anesthetic being used. Some anesthetics produce excellent analgesia at Stage I, while others do not produce any analgesia until Stage III. However, most anesthetics used today are capable of producing Stages III and IV anesthesia as just described. An anesthetic that produces all stages of general anesthesia (I, II, III, and IV) is a complete anesthetic. To be clear, Stage IV is not a therapeutic objective. To keep the patient in Stage III and not Stage IV reflects the skill and experience of the anesthesiology team.
Induction and Maintenance Induction of general anesthesia is the time required to take a patient from consciousness to Stage III. Maintenance of general anesthesia is the ability to keep a patient safely in Stage III. The depth of anesthesia is continually monitored by vital signs, body temperature, ECG, EEG, and general observation of the patient. The methods of continuous monitoring may include computer-assisted devices. The ideal general anesthetic would produce rapid induction and slow maintenance without entering Stage IV anesthesia. In addition, recovery from the ideal general anesthesia would occur rapidly without side effects. Unfortunately, there is no ideal general anesthetic. Some anesthetics are excellent for induction (nitrous oxide, thiopental, and fentanyl citrate-droperidol), whereas others are better for maintenance of general anesthesia. Also, all anesthetics are associated with side effects. Today, anesthesiologists usually employ a combination of anesthetics to meet the needs of surgeons and to minimize patient reaction. (See balanced anesthesia below.) Rapid, smooth induction with well-controlled maintenance is the key to good general anesthesia.
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Types of Anesthesia There are three major categories of anesthesia: local anesthesia, Monitored Anesthesia Care (MAC), and general anesthesia. Local anesthesia inhibits pain sensation in a specific area of the body. (See Chapter 10 for detail including regional anesthesia and nerve block.) The individual remains conscious; sensory nerve conduction is inhibited, but motor neurons are not affected; and sensory nerve function returns to normal (reversible) within minutes to hours of administration. Monitored Anesthesia Care refers to intravenous sedation with midazolam, followed by propofol and/or fentanyl. These drugs rapidly induce a sleepy state where the patient is calm and less responsive to pain before or during a procedure. Diagnostic and surgical procedures that do not require the patient to be unconscious also may use local anesthetics for nerve block to facilitate completion of the procedure. Conscious sedation is a specific term that describes the state where the patient can speak and answer questions but has an altered state of awareness and minimal response to pain when intravenous opioid analgesics and sedatives are administered. The depth of sedation can be light enough to permit patient interaction to instructions or questions, or deep enough that the patient cannot be aroused easily during the procedure. The critical word in this type of anesthesia is monitored. The intravenous anesthetics used in this ambulatory setting have special instructions to alert medical personnel to the need for specific observation, evaluation, and electronic monitoring of the patient through the recovery period. For methohexital and midazolam, continuous monitoring of respiratory (e.g., pulse oximetry) and cardiac function is recommended. Resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation must be immediately available and personnel trained in their use and skilled in airway management should be present. Monitored Anesthesia Care is used in ambulatory surgical centers for minor fracture repair, foot surgery, dental and cosmetic reconstructive surgery, biopsy, and endoscopy (colonoscopy). General anesthesia produces a loss of consciousness in which the patient is totally unaware of pain and does not remember (amnesic) the surgical events or diagnostic procedures on awakening. Another commonly used term to describe anesthesia is balanced anesthesia. Balanced anesthesia is a strategy whereby more than one anesthetic plus muscle relaxants and antianxiety drugs are used to induce and maintain anesthesia. The objective is that each drug complements the action of the anesthetic
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acting at different target sites and requires less absolute CNS depression than a single anesthetic used alone. The anesthesia team and surgical environment in the “not too old days” was a picture of a physician-trained anesthesiologist and a designated room within a hospital specially equipped with monitors and inhalation delivery systems (see Figure 18.2). While this still can be appropriate today, there are many different opportunities for surgery to be performed and general anesthetics to be used outside the hospital. It is fairly common today for anesthesia to be administered for surgical and diagnostic procedures in three areas: a hospital or medical center, an ambulatory surgical center, or a doctor’s or dentist’s office. The type and complexity of the surgical procedures that have moved from the hospital to ambulatory care centers are, in part, a result of improvement in officebased technology (equipment, advanced trained staff) and the need to accommodate patient same-day return to home. It certainly reflects the tremendous increase in elective and cosmetic surgi-centers. The anesthesiology team may be a physician, probably Board certified (American Board of Anesthesiology), nurse, and anesthesia technician. Or it may be a graduate-level advanced trained nurse anesthetist (CRNA, Certified Registered Nurse Anesthetist) or a dental professional. License to administer this class of drugs varies from state to state and continues to be debated, specifically about nonanesthesiologist administration of propofol (see Internet Connection www.endonurse.com). This evolution in the anesthetic arena is important to mention because it points to many places the full range of anesthetics are experienced and employed today. This chapter will focus on drugs with a primary therapeutic action to produce general anesthesia and those drugs that are used in Monitored Anesthesia Care and balanced anesthesia. Figure 18.2 Inhalation Anesthesia
LO 18.1 1
LO 18.2 2
LO 18.3 3
LO 18.4 4
LO 18.5 5
LO 18.6 6
LO 18.7
GENERAL ANESTHETICS General anesthetics are administered by inhalation or intravenous injection. These routes provide rapid delivery of the drug into the blood, which facilitates a smooth induction into anesthesia. General anesthetics’ lipid solubility allows them to dissolve in the blood for distribution to other tissues. Eventually, general anesthetics are carried to the CNS, where lipid solubility permits access across membranes so that the primary pharmacological effect can be produced. The degree of CNS depression resulting in anesthesia is related to the concentration of the anesthetic in the brain.
Inhalation Anesthetics Inhalation anesthetics include volatile liquids such as ether and halogenated hydrocarbons and gases such as nitrous oxide (see Table 18:1). It’s worth mentioning that ether and chloroform appear in Table 18:1 because of their special place in the anesthesiology hall of fame. For example, the signs and stages of anesthesia were worked out from observation of ether’s gradual CNS depression. If sevoflurane had been the anesthetic prototype, the elaborate stages and planes would not have been observed because sevoflurane moves so rapidly to Stage III. By the way, many of the volatile anesthetics used today are ethers. Chloroform is interesting because many murder mysteries and horror films still show the villain placing gauze soaked in something over the victim’s nose and mouth to subdue him or her. It’s chloroform, not sevoflurane! While ether and chloroform have been replaced by newer, relatively more manageable anesthetics, their legacy is still with us. The volatile liquids (halogenated hydrocarbons) are vaporized for inhalation. Those routinely used as general anesthetics include enflurane (Ethrane), desflurane (Suprane), halothane (Fluothane), isoflurane (Forane), and sevoflurane (Ultane). These anesthetics are inhaled through the nose and mouth by means of a face mask (see Figure 18.2). Air (oxygen) must be included in the anesthetic mixture or patients will rapidly develop hypoxia . Anesthesiologists control the anesthetic mixture and rate of delivery of throughout the surgical procedure. Inhalation anesthetics are delivered to the alveoli and then to the blood for distribution to the tissues. These drugs have solubility characteristics where some drugs are more soluble in the blood and like staying there (volatile liquids), or they are not very soluble
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Table 18:1
Side Effects and Uses of General Anesthetics Anesthetic (Trade (Trade Name) Anesthetic
Use
Effect on respiratory system
Nausea & vomiting
Inhalation anesthetics—volatile liquids Chloroform—prototype historical reference
Obsolete
Seldom
Moderate
Desflurane (Suprane)
Maintenance
Highly pungent, irritating, laryngospams in children, bronchodilating
Low
Ether—prototype historical reference
Maintenance
Frequently, increases secretions
High
Enflurane (Enflurane, Ethrane)
Maintenance
Less pungent, some irritation and secretions; bronchodilator
Low
Isoflurane (Forane)
Maintenance
Less pungent, some irritation and secretions; bronchodilator
Low
Halothane (Fluothane)
Maintenance
Less pungent, some irritation and secretions; bronchodilator
Low
Sevoflurane (Ultane)
Maintenance
Bronchodilator, no pungency
Low
Induction
—
Low
Etomidate (Amidate)
Induction
Bronchospasm, laryngospasm, coughing
High
Fentanyl citrate and droperidol—CII*
Induction
Seldom secretions, laryngospasms
Low
Fospropofol (Lusedra)
MAC** sedation
Increased salivation seldom
Low
Ketamine (Ketalar)—CIII
Induction maintenance MAC
Salivation and laryngospasm
High
Methohexital (Brevital, Methohexital)—CIV
Induction maintenance MAC
Bronchial secretions, bronchospasms, laryngospasms
Moderate
Midazolam (Versed)—CIV
Preoperative sedation induction MAC
Increased salivation and bronchospasm seldom
Low
Propofol (Diprivan)
Induction maintenance MAC
Increased salivation seldom
Antiemetic
Thiopental (Pentothal)—CIII**
Induction
Coughing, bronchospasm, salivation
Low–moderate
Inhalation Inhalation anesthetics—gases anesthetics—gases Nitrous oxide Injectable Injectable anesthetics anesthetics
*Scheduled drug indicated by CII, CIII, or CIV. **MAC is monitored anesthesia care.
in the blood and can’t wait to move out of the blood (nitrous oxide, desflurane, sevoflurane). This solubility characteristic is called the blood:gas partition coefficient. The greater the number value of this coefficient (halothane 2.3, enflurane 1.8), the more soluble the drug is in the blood. Nitrous oxide and desflurane are 0.47 and 248
sevoflurane is 0.69. The less soluble drugs have a quicker onset of action because the drugs are ready to cross into the CNS as soon as the circulation gets them there. The more soluble anesthetics have a longer onset of action because they require more anesthetic to dissolve in the blood before enough drug molecules are available to
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cross into the brain. Once in the CNS, the anesthetics modulate neuronal membranes to produce a state of anesthesia. All of the inhalation anesthetics except nitrous oxide produce all stages of general anesthesia; therefore, they can be used for induction and maintenance of general anesthesia. Nitrous oxide (“laughing gas”), although it gets there faster, is not potent enough to maintain Stage III, Plane 3 anesthesia. (That’s just the way it is!) It can be used only for induction of general anesthesia. However, nitrous oxide produces such good analgesia that it is frequently used alone for dental procedures or in combination with other anesthetics. Potency of these drugs is measured by the amount of drug (concentration of drug) in the alveoli that produces a specific effect. The smallest alveolar concentration of drug that keeps the patient immobile reflects the potency of the drug. The standard reference for inhaled anesthetics is MAC or median minimum alveolar concentration that keeps 50 percent of the patients from moving in response to a surgical stimulus (e.g., incision). Of course, the objective is to keep 100 percent of the patients from moving during surgery and this is what the anesthesiologist controls. Remember nitrous oxide? It is not a potent anesthetic because it requires more than 100 percent minimum alveolar concentration to immobilize 50 percent of patients, but it can be incorporated with other anesthetics because it’s a terrific analgesic and less of the second anesthetic would be needed. The volatile liquids all have small MAC numbers like 0.75 percent or 2 percent, indicative of their greater potency. This is an oversimplified description of MAC and blood:gas partition coefficient. It is not intended to explain the physics of gas exchange but to introduce terminology associated with inhalational anesthetics. At the end of the procedure, the face mask is removed and patients quickly exhale the inhalation anesthetics. As a result of exhalation, the blood drug level falls and the patients begin to recover from anesthesia.
Injectable Anesthetics Injectable anesthetics include the barbiturates (methohexital, thiopental), etomidate (Amidate), ketamine (Ketalar), midazolam (Versed), diazepam (Valium), lorazepam (Ativan), and propofol (Diprivan) (see Table 18:1 for injectable anesthetics). Propofol has a significant record of acceptance as an agent for induction, sedation, and maintenance of general anesthesia. It has supplanted the contribution barbiturates made for many years because it has a rapid onset of action and a relatively uncomplicated recovery period. The barbiturate anesthetics can be used for induction or
maintenance of general anesthesia. These drugs are usually administered intravenously because extravascular injections cause pain, swelling, and ulceration. The other injectable drugs in this group (etomidate, midazolam, diazepam, lorazepam) are primarily used for sedation or analgesia (ketamine).
Barbiturates Two drugs are used for rapid intravenous induction of anesthesia and prior to face mask placement for inhalation anesthesia to avoid patient discomfort and experiencing irritation of the upper airway. Thiopental (Pentothal ) and methohexital (Brevital ) are ultrashort-acting barbiturates that induce general anesthesia within 30 seconds. Because thiopental is highly fat soluble, it is redistributed to fatty tissues. The drug accumulates in adipose (fat) tissue and leaves the tissue so slowly that it takes some time for these anesthetics to become metabolized and excreted into the urine. As the anesthetic leaves the adipose tissue, it is redistributed to other organs. Redistribution of the drug leads to residual CNS depression (hangover), mental disorientation, and nausea during the recovery period. Methohexital is more efficiently cleared by the liver and does not result in the same degree of tissue redistribution. It has a shorter elimination half-life and a quicker complete recovery than thiopental. It is the preferred drug among the barbiturates used for anesthesia. Barbiturate anesthetics do not produce analgesia at any dose. In fact, they have been associated with an increased sensitivity to pain when pain is present called hyperalgesia. They are associated with the same side effects and contraindications as other barbiturates (their adverse effects were discussed in Chapter 12). Barbiturate anesthetics may cause laryngospasm or bronchospasm during the postoperative recovery period. It is important to observe patients carefully because they may choke or aspirate fluid into the lungs. An absolute contraindication to the use of thiopental or methohexital is a history or predisposing evidence of status asthmaticus or porphyria. Methohexital is a Schedule IV and thiopental a Schedule III controlled substance because the drugs have a lower potential for abuse, dependence, or addiction relative to the drugs in Schedules I or II and there is an accepted medical use in the United States.
Benzodiazepines Midazolam: Midazolam (Versed ) is a more potent shortacting CNS depressant in the benzodiazepine family (diazepam [Valium], chlordiazepoxide [Librium], and lorazepam [Ativan]). It is the drug of choice when a parenteral Chapter 18 • General Anesthetics
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benzodiazepine is required. It is available for intravenous or rectal administration. The rectal route of administration is particularly useful with uncooperative or agitated children to avoid exacerbating the emotional state because of a fear of needles. Midazolam is frequently administered intravenously prior to short diagnostic or endoscopic procedures to produce conscious sedation and is a standard component in Monitored Anesthesia Care. Midazolam is used for sedation and amnesia and given with neuromuscular blocking drugs for endotracheal intubation. Midazolam is also used for induction of general anesthesia before administration of other anesthetics or to supplement nitrous oxide. Midazolam has been used to reduce emergence agitation following sevoflurane anesthesia. It is chosen over lorazepam and the other benzodiazepines because it has a shorter half-life and no active metabolites to extend the pharmacological effects. Metabolism occurs in the liver and is inhibited by concomitant use of grapefruit juice or ethanol. Midazolam has a rapid onset of action and rapid redistribution to tissues other than the CNS. It produces no analgesia even at anesthetic doses but does provide adequate amnesia. It is metabolized to active metabolites in the liver, which increases its duration of action. Postoperative sedation may be less than the other benzodiazepines; however, it is dependent on the duration of administration, which is directly related to accumulation in tissue during long procedures. Midazolam is given as an oral preanesthetic medication for regional anesthesia and brief therapeutic procedures. Because of the CNS depressant action, preanesthetic opioid medications will potentiate the hypnotic effect of all benzodiazepines. All of these drugs are Schedule IV controlled substances because the drugs have a low potential for abuse, dependence, or addiction relative to the drugs in Schedules I, II, and III and there is an accepted medical use in the United States. The benzodiazepines are the only anesthetic class that have a specific receptor antagonist, flumazenil (Romazicon). Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA receptor. It does not antagonize the effects of any other drugs interacting at other sites on the GABA receptor (barbiturates, volatile anesthetics, or propofol). Flumazenil will reverse the sedative effects of benzodiazepines when an overdose has occurred. Although it has been well tolerated in healthy volunteers and patients who are not dependent on benzodiazepines, it will precipitate withdrawal symptoms in patients who are benzodiazepine dependent. It has caused seizures that are treatable with barbiturates. The association with seizures is a special 250
boxed warning to alert medical personnel to customize the dose to the patient and be prepared to manage seizures if they occur. It is completely metabolized and excreted within 72 hours.
Nonbarbiturates Etomidate: Etomidate (Amidate) is a nonbarbiturate hypnotic drug used for intravenous induction of anesthesia. It is not used for continuous infusion or maintenance anesthesia. Etomidate has no analgesic activity and produces postoperative nausea and vomiting (PONV); however, it exerts less depressant effects on the heart and respiratory centers than do the barbiturates. Because of its cardiorespiratory profile, this drug may be advantageous for use in high-risk surgical patients who cannot tolerate tissue depression. Etomidate is not water soluble and is, therefore, prepared in propylene glycol. This solvent is responsible for causing intense pain on injection. Lidocaine application at the injection site can eliminate this reaction. Etomidate has a rapid onset of action and tissue redistribution limits the duration of action. It is metabolized in the liver to inactive metabolites and excreted by the kidney. While this might contribute to less hangover effect during recovery, etomidate produces nausea and vomiting. Also, it inhibits an enzyme required for the biosynthesis of cortisol in the adrenal gland and cortisol blood levels are reduced during exposure to etomidate. There does not appear to be a significant impact on cortisol synthesis after recovery; however, these side effects often limit the selection of the drug as a maintenance anesthetic. Etomidate is not a restricted drug on the Controlled Substances List. Ketamine: Ketamine (Ketalar) is a short-acting nonbarbiturate dissociative anesthetic that produces good analgesia even at nonanesthetic doses and loss of memory (amnesia) but does not relax skeletal muscles. In fact, ketamine increases muscle tone. Patients appear to be awake, eyes are open with alternating smooth and fast object tracking (nystagmus), limbs may move, but they do not respond to painful stimulation. Ketamine inhibits the excitatory pathway by a direct interaction with the NMDA receptor (see Mechanism of Action). It is thought to act primarily upon the limbic system so that very little respiratory and cardiovascular depression is produced. In fact, ketamine stimulates the sympathetic nervous system so blood pressure and heart rate may be elevated during the anesthesia. (See Physiological Effects below for ketamine’s cardiovascular activity). Ketamine is not the anesthetic of choice in patients where a significant increase in blood pressure would be hazardous. Ketamine relaxes bronchioles and is a good anesthetic for patients with asthma or bronchospasms.
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Ketamine has an onset of action within 3 minutes and a duration of 20 minutes from a single administration. Low-dose ketamine combined with either midazolam or propofol is administered before injection of local anesthetics in outpatients undergoing a variety of surgical procedures. This short-acting anesthetic is rapidly metabolized in the liver to mildly active metabolites. It can be given intramuscularly or intravenously to induce anesthesia. Vivid dreams and hallucinations usually occur during the recovery period and can last for 24 hours after ketamine administration. This occurs most often in adults. Children experience this less frequently and with a milder reaction. Other ketamine-induced effects include out-of-body experiences, increased auditory sensitivity, and euphoria. In a small percentage of patients, delirium occurs (emergence delirium). This is a sudden state of severe confusion with rapid changes in brain function, sometimes associated with hallucinations. Severe reactions are treated with benzodiazepines or short-acting barbiturates. Another ketamine-induced effect is an increase in intraocular pressure, making it not the anesthetic of choice for ocular surgery. Ketamine is chemically related to phencyclidine, a hallucinogen of high abuse potential. Ketamine does appear as a street drug for nonmedical, recreational use. Ketamine is a Schedule III drug because its potential for abuse is less than the drugs in Schedules I and II, it has an accepted medical use in the United States, and abuse of the drug may lead to moderate or low physical dependence or high psychological dependence. Propofol: Propofol (Dipravan) is the most commonly used parenteral anesthetic in the United States. Propofol was first introduced as a sedative-hypnotic and has since frequently replaced barbiturates as the sedativehypnotic of choice in the anesthesia forum. Propofol is used to initiate and maintain MAC sedation during diagnostic and surgical procedures. It is used for MAC sedation in conjunction with local or regional anesthesia. It is also used for induction or maintenance of anesthesia as part of a balanced anesthetic technique for inpatient and outpatient surgery in adults and children at least 3 years of age. As a complete anesthetic it is able to fully depress the medulla, resulting in death. Like all complete anesthetics, it has a narrow margin of safety; the pharmacologic dose is only a few cc’s from the lethal dose. This is especially true to propofol. Propofol is not water soluble and, therefore, is prepared as an emulsion in soybean oil, glycerol, and purified egg phosphatide. The drug rapidly reaches the CNS with an onset of action in a few seconds. Propofol is used in subanesthetic doses for conscious sedation, but it is not regarded as an analgesic. Occasionally, during
induction, there is muscle twitching attributed to an invoked excitatory response. Propofol does depress cardiovascular and respiratory activity similar to or greater than the barbiturates. Hypotension is more prominent than with other anesthetics because it decreases vascular resistance by inhibiting sympathetic tone on vascular smooth muscle, depresses the baroreceptor response to hypotension, and depresses cardio contractility. When used in subanesthetic doses for conscious sedation, propofol depresses the reflex response to increased carbon dioxide and reduced oxygen. These are expected effects with a complete anesthetic and not the reason it is the most used parenteral anesthetic. Propofol does not rely on tissue redistribution for recovery but is cleared by the liver to inactive metabolites and excreted by the kidney. The duration of action is short, being controlled by readministration of the drug at safe intervals or continuous infusion. There is no hangover effect from tissue redistribution and active metabolites. Recovery to a clear mental state with no nausea and vomiting and minimal respiratory or cardiac depression is shorter compared to other anesthetics. Unique among the anesthetics, propofol is the only anesthetic that is antiemetic. Evidence in the literature demonstrates that patients who received propofol don’t develop nausea and vomiting up to 72 hours after exposure, and analgesic consumption and recovery time are reduced. This profile makes propofol an excellent anesthetic for outpatient procedures in all types of surgical settings and contributes to its popularity. There are some undesirable effects associated with propofol such as pain on injection attributed to a reaction to the emulsifiers. This can be avoided by administering lidocaine with propofol. Strict aseptic technique during handling is required because the vehicle is capable of supporting bacterial growth. Fever, infection, life-threatening illness, and death have occurred due to contamination and patient inoculation. Sodium metabisulfite or EDTA has been added to propofol prefilled syringes and single-use vials to inhibit bacterial growth. The sodium metabisulfite may produce an allergic reaction in sensitive individuals and asthma patients. At this time, propofol is not a controlled substance; however, the abuse among medical health care professionals has been the basis for placing a brand new sedative-hypnotic, fospropofol, into Schedule IV. Fospropofol (Lusedra) has recently (December 2008) been introduced for MAC sedation in patients undergoing diagnostic or surgical procedures. It is a water-soluble prodrug for propofol prepared in a preservative-free solution. The goal was to replace the lipid base and the associated irritant reaction and microbial growth Chapter 18 • General Anesthetics
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environment yet retain adequate delivery of the active drug. Following intravenous injection, alkaline phosphatases, present in all tissues, convert fospropofol to propofol. While there is a molecule-for-molecule conversion, it appears that the converted propofol is more potent (on EEG and clinical signs of hypnosis) than the one delivered in a lipid emulsifier. Liberated propofol has shorter distribution and elimination half-lives compared to the lipid-formulated propofol. There is variability in the response to a given dose so that dose titration to the drug effect is needed, but there is a delay in observation of the pharmacological effect. This provides an opportunity for administering more drug too soon and overdosing the patient. Fospropofol is a water-soluble intravenous preparation; however, it might be taken orally as a liquid, making it much easier to abuse than the propofol emulsion, especially as a potential street drug. This is the reason the FDA recommended fospropofol be classified as a controlled substance. Studies investigating the recovery profile of propofol have reported that patients anesthetized with propofol wake up elated, euphoric, and feeling refreshed. Laboratory studies confirm that subanesthetic doses of propofol increase dopamine in the areas of the brain associated with reward and reinforcement behavior, like other Schedule IV drugs. Because of the shorter half-life, repeat dosing may be reinforced, creating a “stacking effect” and potential overdose. Medical professionals don’t usually take the drug to get high because it puts them instantly to sleep. Instead, it is taken to relieve stress; users wake up feeling refreshed. Dependence from propofol is mostly psychological, characterized by craving, loss of control over the amount and frequency of drug required to achieve the desired effect, and continued use despite adverse consequences. Physical dependence has not been identified, although withdrawal phenomena have been reported after prolonged use.
Alpha2 Adrenergic Agonist Dexmedetomidine (Precedex) is a novel drug that is used for short-term procedural sedation. It is a potent α2 adrenergic agonist. Receptors for alpha2 are found in the peripheral and central nervous systems, platelets, and a variety of organs, including the liver, pancreas, kidney, and eye. Responses mediated by these receptors vary with location. Presynaptic activation of the alpha2 adrenergic receptor suppresses calcium entry into the nerve terminal and inhibits the release of norepinephrine, terminating the propagation of pain signals. Postsynaptic activation of α2 adrenergic receptors in the CNS inhibits sympathetic activity, resulting in decreased blood 252
pressure and heart rate. Together these effects produce analgesia, sedation, and reduced anxiety. When used during induction, dexmedetomidine potentiates the anesthetic effects of intravenous, volatile, and regional block anesthetics. It also reduces the requirement for supplement opioid analgesics and midazolam. This means less individual sedative, analgesic, or anesthetic is required to achieve the good anesthesia and without additional respiration depression. The benefits of dexmedetomidine continue in its activation of receptors in other areas. Decreased salivation, decreased GI secretion and bowel motility, increased glomerular filtration, and decreased insulin release from the pancreas are some of its stress-reducing effects in the perioperative period. This drug is administered by continuous infusion so the onset of action is fast and the duration of action after termination of the infusion can be up to 4 hours. The drug is completely metabolized in the liver and its metabolites excreted in the urine and feces. The most frequent adverse effects that occur with dexmedetomidine are hypotension, bradycardia, and dry mouth, which warrant close monitoring through the recovery period. Dexmedetomidine is used for procedural sedation. It is also used for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive-care setting. It should be administered by continuous infusion not to exceed 24 hours.
Opioids and Droperidol When a mixture of an opioid analgesic (fentanyl) and a tranquilizer (droperidol) is administered, neuroleptanalgesia is produced. This type of anesthesia provides excellent analgesia while patients remain conscious. This combination cannot produce unconsciousness (neuroleptanesthesia) unless a third anesthetic (nitrous oxide) is added. Fentanyl is one of the drugs selected for use in balanced anesthesia and conscious sedation. Fentanyl is a rapid-acting synthetic opioid effective in blunting the sympathetic reflex response to laryngoscopy and intubation. Fentanyl and droperidol are eventually metabolized by the liver. Unusual side effects that occur with the use of droperidol are extrapyramidal symptoms. Occasionally, a parkinsonian syndrome—uncontrolled movements of the tongue and head—occurs. The fentanyl and droperidol may be administered intramuscularly or by slow intravenous injection. If an opioid analgesic is prescribed following this kind of anesthesia, the dose of the opioid may be significantly reduced to one-fourth of the recommended dose because these drugs have a synergistic action on the CNS. Droperidol has a special warning (black box)
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associated with its use because it has been reported to lengthen the QT interval in the heart, potentially predisposing patients to the development of fatal cardiac arrhythmias. Fentanyl is a Schedule II drug because it has a high potential for abuse and may lead to severe psychological or physical dependence. It has a currently accepted medical use in the United States. LO 18.3
MECHANISM OF ACTION
decreases neuronal membrane “excitability.” GABA A receptors are continually active, so anything that interacts with them has a continual response. Inhaled anesthetics, benzodiazepines, barbiturates, etomidate, and propofol bind with GABA A receptors and enhance the GABA hyperpolarization. The barbiturates and propofol also may directly increase the chloride ion channel opening sustaining the GABA inhibitory action. These anesthetics enhance the inhibitory (GABA, glycine) pathways. Besides the inhibitory GABA receptor system, anesthetics may interface with membrane pore proteins that facilitate potassium ion (K+) movement. Throughout the CNS are potassium ion channels. When potassium ions move out of the cell, membranes are hyperpolarized, inhibiting depolarization. Another way to depress CNS function is to inhibit the excitatory neurotransmitter, glutamate, in the brain. The NMDA (N-methyl D -aspartate) receptor is a glutamate receptor that facilitates positive ion (cation, Na+, Ca++, K+) movement through its channel, depolarizing the postsynaptic cell (excitation). Nitrous oxide, propofol, and ketamine antagonize NMDA receptors, thereby blocking cation movement and depolarization.
All general anesthetics are CNS depressants, but how neuronal function is modulated differs with each drug. This class is so dissimilar in chemical structure that it was believed for a long time that these drugs could not interact with receptors, certainly not an individual receptor. In fact, it was held that interference with CNS conduction by anesthetics was probably due to the ability of the drug to cross the blood-brain barrier (lipid solubility) and alter the membrane dynamic (perturb the membrane). During the past several years, there has been a dramatic change in understanding of the mechanism of action of anesthetics. Not only do anesthetics interact with a variety of receptors, the interaction at multiple receptors can synergize (enhance) the anesthetic effect when drugs are used in combination to maintain anesthesia. Figure 18.3 There is considerable evidence that most general anesthetics inhibit CNS General Anesthetic Sites of Drug Action on GABA and NMDA activity by interacting with membrane Receptors ion channels (neurotransmitter-gated ion channels), especially through actiExtracellular Extrac Ext racell rac ellula ell ularr ula Extracellular vation of gamma-amino butyric acid (GABA) receptors. GABA is the princiCl⫺ Na⫹, Ca2⫹ IIons pal inhibitory neurotransmitter within GABA the brain, and glycine is the inhibitory  GABA transmitter in the brainstem and spinal ␣ ␥ ␣ Benzodiazepines  cord. The GABA receptors are a superFlumazenil family of membrane-bound proteins (see Zolpidem Figure 18.3). When GABA and glycine bind to their respective receptors, pores Barbiturates (ion channels) open through the lipid membrane, allowing passive movement Ion channel Propofol of small ions. This ion movement changes the potential across the membrane, anne nnel nel P Prot rotein rot i ((b b)) GAB b G GA ABA Rece R ecepto ece ptorr pto (c) NMDA NM NMD (a) Channel (b) (c) Glutamate Protein GABA Receptor affecting conductivity of the cell. hannel han nel pr prote oteiin in Inhibi Inh nh nhibi hibi ibitttory; ib Rece Rec e Receptor A cchannel protein Inhibitory; Excitatory; depolarizes that is constantly hyperpolarizes the General anesthetics bind with the the membrane. open and allows membrane. Barbiturates, GABA A (inhibitory) receptor and cause Ketamine, nitrous solutes to pass benzodiazepines, − chloride ions (Cl , negative ion) to move oxide, and propofol into and out of etomidate, propofol, antagonize glutamate the cell. and volatile anesthetics across the membrane into the cells, action. enhance GABAA. making the membrane hyperpolarIntracellular Intracellular ized (can’t respond to stimulation). This Chapter 18 • General Anesthetics
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These drugs also enhance the opioid mu receptors, which will be discussed in Chapter 19 on opioid analgesics. Volatile anesthetics modulate both excitatory and inhibitory synaptic transmission. The most potent inhaled agents and most intravenous agents enhance the inhibitory GABA A and glycine receptors and depress other excitatory neuronal nicotinic acetylcholine (ACH) receptors. When intravenous and inhalation anesthetics are used together, there is a clinical benefit to the patient. The minimal alveolar concentration of the volatile anesthetics required to induce anesthesia is less when intravenous anesthetics are enhancing the inhibitory receptors and antagonizing excitatory receptors. LO 18.2 2
LO 18.7
PHYSIOLOGICAL EFFECTS OF ANESTHETICS The primary therapeutic action of inhalation and injectable anesthetics is on the CNS, for the patient to be in an anesthetic state. At low doses or low concentrations in the blood, these drugs relieve anxiety and produce sedation. At the appropriate drug level to produce anesthesia, however, all of these drugs also influence a variety of other tissues. Selection of the proper anesthetic may depend on evaluating the drug’s spectrum of actions such as alteration of cardiac, respiratory, or hepatic function.
Central Nervous System The primary nonanesthetic effects of general anesthetics on the CNS involve regulation of cerebral blood flow, change in intracranial pressure, and seizure induction.
Inhalation Anesthetics In general, all nervous tissue is depressed by inhalation general anesthetics. Voluntary (motor) and involuntary (autonomic) systems are inhibited in the state of surgical anesthesia. These drugs dilate cerebral blood vessels and may increase intracranial pressure. This group of anesthetics might not be a good choice for use in patients who already have increased intracranial pressure from cerebral edema or tumors, except that the drugs vary in their effect on cerebral blood flow. Halothane produces the greatest increase in intracranial pressure. Isoflurane, desflurane, enflurane, and sevoflurane are associated with less intracranial pressure elevation and are drugs of choice for neurosurgery. Enflurane and sevoflurane have been associated with increased seizure activity and are not recommended for patients with seizure disorders, but desflurane and isoflurane have successfully reduced seizures in patients with refractory status epilepticus. 254
Injectable Anesthetics Methohexital, propofol, etomidate, midazolam, diazepam, and lorazepam decrease intracranial pressure and cerebral blood flow. With barbiturates this is considered a protective effect against local cerebral ischemia. It may be an advantage with any of these drugs when used in neurosurgery. Ketamine increases intracranial pressure and cerebral blood flow. This may be a contraindication to its use in patients with increased intracranial pressure. Only ketamine, barbiturates, and benzodiazepines have anticonvulsant activity because they hyperpolarize neuron membranes through their respective receptor interactions (see Figure 18.3). This has a beneficial seizure suppressant action during surgery.
Respiratory System Respiratory function is depressed through a central action by most anesthetics (but not ketamine). With inhalation anesthetics oxygen deprivation during the procedure does not occur because ventilation is controlled by the anesthesiologist. Residual effects of anesthetics may result in postoperative ventilatory failure and hypoxia. Impaired respiratory control may be caused by depression of central ventilatory control, by depression of peripheral sensory organs (carotid body chemoreceptors), or by impaired control of the pharynx and the upper airways. On the other side the discussion is how muscle spasms within the respiratory system impact other critical tissues such as the brain. Stimulation of the airway causes a sympathomimetic reflex response, whether there is physical contact with implements (laryngoscope) or an anesthetic-induced spasm. This stimulation can result in a transient increase in intracranial pressure (ICP). Simply coughing and gagging may facilitate transmission of intrathoracic pressure to the cranium. The principal issues with drug-induced interference in the respiratory system involve residual postoperative hypoxia, the production of secretions, and muscle spasms along the respiratory tract.
Inhalation Anesthetics All of the volatile liquid anesthetics are good bronchodilators because they directly relax bronchiolar smooth muscle. They inhibit smooth muscle contractility and interrupt neural conduction involved in the reflex spasticity. This can be of value for patients with a history of chronic obstructive pulmonary disease, bronchitis, or asthma. These anesthetics have been used to treat status asthmaticus when other treatments were not effective. All of these anesthetics except sevoflurane irritate the respiratory lining, causing coughing, increased salivary and mucus secretions, and laryngospasm. Pungency is
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the term used to describe this characteristic ability to irritate the respiratory tree. Desflurane is the most pungent, strong airway irritant in conscious patients. Studies have reported that study participants pull off the mask and complain about the irritation after a few breaths. For this reason, an intravenous anesthetic is used to induce anesthesia, and then desflurane maintenance follows. All of the drugs in this class except sevoflurane stimulate mucus secretion. Increase in saliva and mucus secretions is important because secretions can interfere with the transfer of gases from the alveoli to the blood and impact oxygenation. These drugs also inhibit the microcilia that line the respiratory tract to move secretions. This further complicates the clearance of secretions. Sevoflurane is an anesthetic of choice for induction with an inhalation agent because it lacks pungency, has no irritating effects on the respiratory tree, and does not promote secretion production. It also doesn’t depress the heart (see below).
Injectable Anesthetics Benzodiazepines and barbiturates produce a dosedependent respiratory depression. These drugs decrease respiratory rate and tidal volume. Benzodiazepines (midazolam) exert relatively less depression than the barbiturates, which can produce transient apnea. Barbiturates can cause a deep depression of the medullary respiratory center. Patients with underlying chronic obstructive pulmonary disease are more susceptible to the depression, even at doses that would be considered therapeutic in healthy individuals. Fatality from barbiturate and benzodiazepine overdose is usually secondary to respiratory depression. Reflex responses to increased carbon dioxide (hypercarbia) and decreased oxygen (hypoxia) are depressed. This effect persists in the postoperative recovery period so patients must be closely monitored to ensure adequate ventilation is not compromised. Barbiturates lightly depress laryngeal reflexes so that any stimulation (secretions, intubation) can result in coughing and laryngospasm. Histamine, released from mast cells by these drugs, produces bronchospasm. These drugs are used with caution in patients with preexisting airway resistance conditions. Etomidate has the same respiratory profile as the barbiturates. Propofol is a respiratory depressant just as described for barbiturate anesthetics. It dampens the response to hypoxia and hypercarbia and can produce apnea. Unlike the other drugs, it is not associated with histamine release and it depresses reflexes associated with coughing and spasms. This means wheezing, coughing, and bronchospasm are less common with this drug and it can be safely used in asthmatic patients.
Ketamine dilates bronchial smooth muscle and maintains muscle tone and respiratory reflexes. This is valuable in the recovery period as the patient’s chemoreceptors will respond appropriately to stimuli of hypoxia or hypercarbia. Ketamine does not produce respiratory depression, unlike all the other anesthestics, and is often selected as an alternative to opioids (respiratory depressants) when analgesia is required. Ketamine does increase tears and salivation, which could precipitate laryngospasms, but this is not a significant problem with its use. Ketamine is the induction agent of choice in patients with bronchospasm. Studies have shown that when ketamine is used in patients with asthma who are dependent on ventilators, respiratory acidosis and airway pressures are decreased.
Cardiovascular System The myocardium (heart muscle) and blood pressure may be depressed by general anesthetics. However, the degree of depression varies with the anesthetic used. Blood pressure may decrease because sympathetic tone is inhibited, whereas heart rate may increase due to vagal inhibition. Occasionally, catecholamines are secreted from the adrenal medulla in response to the stress of surgery. These circulating catecholamines may counteract the myocardial depression of the anesthetic or ventricular arrhythmias may occur because some anesthetics sensitize the heart to the catecholamine stimulation. Cardiovascular depression may occur following depression of the medullary vasomotor centers; patients with underlying congestive heart failure (CHF) are more susceptible to these effects. At higher doses, cardiac contractility and vascular tone are compromised, which may cause cardiovascular collapse.
Inhalation Anesthetics In general, all of these drugs produce peripheral vasodilation and decrease blood pressure. The decrease in blood pressure is proportional to the amount of drug in the lung (alveolar concentration). To decrease blood pressure, either the heart is depressed (reduced cardiac output) or the peripheral vascular musculature is relaxed (peripheral vasodilation). Desflurane, sevoflurane, and isoflurane depress the peripheral vasculature to reduce blood pressure. With these drugs there is no reduction in cardiac output. In fact, these drugs may produce a transient increase in heart rate. Isoflurane and desflurane can cause transient tachycardia and hypertension through stimulation of the sympathetic nervous system. This can be a positive factor for selection of these anesthetics in patients already predisposed to hypotension. Enflurane and halothane have a primary effect on the Chapter 18 • General Anesthetics
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cardiac muscle. These drugs depress cardiac contractility and cardiac output, resulting in lower blood pressure. Halothane directly sensitizes the myocardium to catecholamine stimulation, which can predispose the patient to cardiac arrhythmias. Nitrous oxide produces less myocardial depression than the volatile anesthetics and desflurane and sevoflurane are associated with minimal to no myocardial depression.
Injectable Anesthetics Benzodiazepines have little effect on the cardiovascular system or autonomic nervous system compared to other anesthetics. Methohexital and propofol produce a decrease in blood pressure because of peripheral vasodilation and decreased myocardial contraction. The decrease in blood pressure is dose related and produced whether using a large single dose or continuous infusion of the drug. The change in blood pressure is usually counteracted by autoregulation (baroreceptor reflex) through the sympathetic nervous system; however, barbiturates and propofol also depress the baroreceptor reflex. This contributes to the development of hypotension. Propofol causes more pronounced hypotension than the barbiturates. In healthy patients, this is generally manageable and without significant sequelae. Etomidate has a different profile. Etomidate has no depressant effect on blood pressure or cardiac output and mildly increases heart rate. It also decreases oxygen consumption by the heart but does not alter coronary perfusion. This means the heart isn’t working as hard. This drug may be favored for its cardiostability and, for this reason, can be selected for patients with coronary artery disease or cardiomyopathy. The unique property of acutely decreasing intracranial pressure while maintaining normal hemodynamics places etomidate in a class by itself among induction agents. Ketamine increases heart rate, blood pressure, and cardiac output by stimulating the sympathetic nervous system. It also increases oxygen consumption of the myocardium.
Skeletal Muscle Depression of pyramidal systems and spinal reflexes causes skeletal muscle relaxation in Stage III (Plane 3) anesthesia. Certain anesthetics produce additional skeletal muscle relaxation by inhibiting neuromuscular function. Acetylcholine is prevented from interacting with skeletal muscle membrane–bound receptors.
Inhalation Anesthetics All volatile anesthetics produce a dose-related relaxation of skeletal muscle. When used alone, inhalation 256
anesthetics facilitate muscle incision and manipulation through relaxed tone exerted at the muscle receptor level. They potentiate the neuromuscular blockade of concomitantly administered depolarizing and nondepolarizing neuromuscular blocking drugs. This may delay recovery of muscle function and coordination. In the postoperative period, assisted ventilation may be required if muscle weakness persists, with the potential for causing airway obstruction and aspiration. Nitrous oxide does not relax skeletal muscle; it has been reported to increase skeletal muscle tone.
Injectable Anesthetics Benzodiazepines inhibit spinal afferent pathways to produce skeletal muscle relaxation. These drugs are used to interrupt excessive contractions in spasticity disorders and dyskinesias. The site of interaction on the GABA receptor is at a locus separate from that which produces sedation and hypnosis. Propofol does not potentiate neuromuscular blockade of the neuromuscular blocking drugs, while ketamine increases skeletal muscle tone.
Nausea and Vomiting (PONV) Postoperative nausea and vomiting (PONV) are the most common side effects associated with the use of general anesthetics. PONV is evaluated as three types of patient responses. Nausea is the feeling or urge to vomit without expectorating. Vomiting is oral expulsion of gastric contents. Retching is an unproductive effort to vomit. These events can range from mildly annoying nausea to increasing severity of muscle involvement (contraction of the stomach, abdomen, intercostals, larynx, and pharynx) accompanied by increased salivation, vasomotor disturbance, and sweating. The importance of controlling or avoiding these physiological responses ranges from making the patient more comfortable to interruption of potential cardiovascular and vasomotor changes resulting from vomiting-induced dehydration and electrolyte changes. Anesthetic agents increase the sensitivity of the vestibular center in the inner ear. Rapid position change or movement of a sensitive patient may lead to the development of PONV. When a person becomes disoriented due to motion, the vestibule sends a signal through nerves to the vomiting center in the brain, and vomiting occurs. These effects frequently occur during recovery, making patients uncomfortable and predisposing the patient to potential aspiration. There is evidence that volatile anesthetics are emetogenic (induce vomiting) and that there are no meaningful differences between halothane, enflurane, isoflurane, sevoflurane, and desflurane.
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Among the injectable anesthetics, etomidate is the most likely to produce PONV. Propofol is the only anesthetic to have evidence of reducing PONV. Used alone or in combination with other inhalation or intravenous anesthetics, propofol has been reported to reduce the incidence of PONV. It is characterized as an antiemetic among anesthesiologists, although it is not used for that purpose in other medical areas. (See further discussion of antiemetics under Adjuncts to General Anesthesia).
Hepatic and Renal Systems Inhalation Anesthetics While volatile anesthetics are exhaled as a route of elimination from the body, most of these drugs and the intravenous anesthetics are metabolized to some extent in the microsomal enzyme system of the liver. The volatile anesthetics temporarily reduce renal and hepatic blood flow, glomerular filtration, and urine output. Other than the temporary inhibition in urine output, there are usually no significant residual effects associated with anesthetic use and renal and hepatic functions. These drugs are used in patients with renal or hepatic disease. The most significant and not frequent event associated with volatile anesthetics is hepatitis. There are two types of postoperative residual effects on liver function: Type I, mild, and Type II, severe hepatitis. Type I is a self-limiting event associated with elevated liver transaminases, lethargy, fever, and nausea in 10 to 20 percent of patients. This mild hepatitis is attributed to an alteration in hepatic blood flow during surgery reducing oxygenation to the hepatocytes. Type II is a life-threatening condition in which liver necrosis occurs and death may ensue. Type II is an immunologic-mediated condition that requires that the patient had to have previously been exposed to a volatile anesthetic resulting in antibody production. The volatile anesthetics, except for sevoflurane, are metabolized in the liver to trifluoroacetate (TFA). In the rare case (1 in 30,000 patients), TFA irreversibly binds to hepatocyte proteins and becomes recognized as a foreign agent to which antibodies are made. There is no diagnostic test to determine which patients are predisposed to developing hepatitis. The occurrence is unrelated to the type or duration of surgery and occurs more frequently in women over 40 years old. Fever, rash, and jaundice may not appear for up to 2 weeks after exposure. A thorough medical history indicating prior evidence of hepatic dysfunction during the course of the recovery on exposure to volatile anesthetics is the only way to identify a potential occurrence of hepatitis. Volatile anesthetics are contraindicated in patients with a known sensitivity to these anesthetics. Despite the infrequent occurrence of
hepatitis (first associated with halothane), the availability of other anesthetics has virtually replaced halothane use. Desflurane and sevoflurane have very little association with drug-induced Type II hepatitis.
Injectable Anesthetics Most of these drugs are metabolized to some degree by the microsomal enzyme system in the liver. Elimination of the drug and its effects depends on the liver and kidneys. In general, there is little effect on these organs. Barbiturates reduce the glomerular filtration rate and hepatic blood flow during their anesthetic activity, but organ function returns to its preexposure state at the end of the procedure. LO 18.6
ADJUNCTS TO GENERAL ANESTHESIA In addition to the anesthetic agents, a variety of different drugs are routinely used before and after surgical procedures, as outlined in Table 18:2. Preanesthetic and postanesthetic medications are administered to aid induction of general anesthesia, counteract the side effects of anesthetics, or make recovery safe and more comfortable for patients. Many people approach surgery with fear and apprehension; usually there is intense anxiety about the existing medical problem and concern about the outcome of the operation. Some individuals also experience severe pain as a result of their medical condition. Anxiety and CNS stimulation tend to counteract a smooth induction into anesthesia. Therefore, CNS depressants, such as opioid analgesics, benzodiazepines, tranquilizers, or sedative-hypnotics may be administered before surgery. Often, these adjunct medications are given the evening before so that patients are groggy and unaware of the preparations being carried out prior to surgery. For procedures in an ambulatory or dental surgery setting, the preanesthetic protocol, other than fasting, bowel cleansing, or discontinuance of medications, may begin on site.
Postoperative Nausea and Vomiting (PONV) Postoperative nausea and vomiting are definitely unwanted events associated with the anesthesia. It is reported to occur in 70 to 80 percent of patients at high risk to develop PONV, and up to 35 percent of all patients. Many patients complain about PONV from a prior procedure or surgery, ranking it among the top three postoperative events they do not want to experience again. Efforts to optimize the prophylactic treatment (preanesthesia) for PONV have identified several Chapter 18 • General Anesthetics
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Table 18:2
Adjunct Medications Used with Anesthetics Pharmacological class
Administration
Reason for use
Analgesics (opioid )
Preanesthesia, postanesthesia
Relieve pain and produce sedation
Antianxiety agents (benzodiazepines)
Preanesthesia
Decrease apprehension
Antiarrhythmic drugs
During surgery
Control arrhythmias
Antibiotics
Preanesthesia
Decrease infection
Anticholinergics
Preanesthesia, during surgery
Decrease salivary and bronchial secretions, prevent bradycardia
Antiemetics
Preanesthesia, postanesthesia
Block postoperative nausea and vomiting
Cholinergic drugs
Postanesthesia
Relieve urinary retention
Sedative-hypnotic drugs (short-acting agents)
Preanesthesia
Decrease apprehension
Skeletal muscle relaxants
Beginning of procedure, During surgery
Facilitate endotracheal intubation Sustain skeletal muscle relaxation
Tranquilizers
Preanesthesia, postanesthesia
Sedation, control nausea and vomiting
factors associated with patients at risk: female gender, obesity, a history of PONV or motion sickness, anticipated use of opioids or large doses of neostigmine, type of surgery and anesthetic, and duration of the procedure. PONV is almost always self-limiting and nonfatal, but it can induce dehydration, electrolyte imbalance, suture tension and dehiscence, and life-threatening airway compromise. Each vomiting episode delays discharge from the recovery room and, when ambulatory care centers are considered, may result in an unplanned overnight admission rather than a same-day return to home. This impacts patient satisfaction, comfort, and procedural expense. Induction of vomiting is a well-orchestrated interaction involving two control centers (vomiting center and chemoreceptor trigger zone) and at least five neurotransmitters such as serotonin, acetylcholine, dopamine, histamine, and substance P and their respective receptors located in the control centers (see Figure 18.4). Among the afferent inputs to the vomiting center is direct information from the vagus (cholinergic) nerve relaying conditions in the gastrointestinal tract (distension), the vestibular system relaying conditions from the inner ear regarding balance and motion, and the chemoreceptor 258
trigger zone (CTZ) assessing noxious chemicals in the circulation. Information about a harmful environment, ingestion of toxic substances, or accumulation of metabolic toxins triggers the release of these neurotransmitters in the vomiting center and CTZ. This may bring about coordinated contraction of abdominal and respiratory muscles to expel the culprit through the mouth.
Dopamine D2 Antagonists The drugs that have shown the best efficacy as antiemetics in the perioperative period antagonize specific receptors in the vomiting center or CTZ. For years, droperidol was the gold-standard preanesthetic antiemetic. It is effective in low doses as a single agent antiemetic for prophylaxis and treatment and inexpensive compared to the newer receptor-specific alternatives such as serotonin antagonists. Droperidol is a tranquilizer sedative that is a strong dopamine D2 receptor antagonist. The hypothesis is that droperidol occupies the postsynaptic GABA receptor so that dopamine accumulates in the synapse. This alters the normal balance between acetylcholine and dopamine and inhibits CTZ transmission to the vomiting center. It is extensively metabolized and excreted in the urine and feces. The best antiemetic
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Figure 18.4
Centers and Receptors in the Brain Associated with Nausea and Vomiting
Vestibular system Muscarinic (ACH) M1 receptor
Fourth ventricle
Chemoreceptor trigger zone
Vagus nerve Gastrointestinal tract and heart
Vomiting center
Chemoreceptor trigger zone (area postrema) Chemoreceptors D2 receptor NK1 receptor 5HT3 receptor Vomiting center (nucleus of tractus solitarius) H1 receptor M1 receptor NK1 receptor 5HT3 receptor
Antiemetic Drugs M1 antagonists: scopolamine, H1 antihistamines
Antiemetic Drugs H1 antihistamines—diphenhydramine, dimenhydrinate M1—scopolamine, antihistamines NK1—Aprepitant D2—droperidol, promethazine, prochlorperazine 5-HT3—ondansetron, dolasetron, granisetron
Parasympathetic and motor efferent activity Mechanoreceptors Chemoreceptors 5HT3 receptor Nausea, vomiting
effect is observed when droperidol is given at the end of surgery, rather than as a preanesthetic medication. Its onset of action after intramuscular injection is 3 to 5 minutes and its duration of action is 4 to 12 hours. Although still available as a generic formulation, droperidol use has declined since its cautionary warning regarding a potential association with fatal cardiac arrhythmia. It should be noted that challenges were made to distance the potential of life-threatening cardiac arrhythmia from droperidol through its otherwise relatively uneventful history of fatal arrhythmia during its use estimated as fewer than 10 fatal arrhythmias in 1 million patients treated. While the caution remains in the drug labeling instruction for use, droperidol is still considered among the choices for first-line therapy of PONV. Droperidol is not the antiemetic of choice for patients predisposed to developing cardiac arrhythmia or changes in cardiac function. Otherwise the adverse effects include drowsiness, sedation, and hypotension; because it’s an alpha-adrenergic receptor blocker in the vascular smooth muscle and CNS, akathesia and, rarely, extrapyramidal syndrome (dyskinesias, akinesia) occur. The akithesia and extrapyramidal symptoms are related to the dopamine effect.
Serotonin (5HT3) Antagonists The serotonin antagonists, first-line therapy for PONV, include ondansetron (Zofran), dolasetron (Anzemet), and granisetron (Kytril, Granisol). These serotonin receptors are located on vagal nerve terminals, neurons in the GI tract, where they regulate GI secretions, colon motility, and transmission of visceral pain, and centrally in the CTZ (see Figure 18.4). There is a high degree of receptor specificity as the (5HT3) antagonists do not interact with other serotonin receptors, or with cholinergic or dopamine receptors. Ondansetron has an effective duration of 4 to 6 hours, whereas granisetron has a duration of about 12 to 14 hours. An oral disintegrating tablet has been developed for ondansetron to be used at home following discharge. This class of drugs seems to have a ceiling effect so that continued dosing in the presence of unresolved PONV does not further reduce the symptoms. Subsequent treatment strategy is to move to another type of antiemetic agent. These drugs are well absorbed orally, metabolized in the liver, and excreted in the urine and feces. Dolasetron has an effect on cardiac conduction observed as prolongation of the PR and QTc intervals (as with droperidol) and QRS widening, all attributed to blockade of sodium channels. It is worth noting
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that there is no cautionary warning (black box) that accompanies the use of this drug. Nevertheless, patients with hypokalemia or hypomagnesemia, patients taking diuretics with the potential for inducing electrolyte abnormalities, patients with congenital QT syndrome, and patients taking antiarrhythmic drugs or other drugs that might lead to QT prolongation are not candidates for receiving dolasetron. The other (5HT3) antagonists exhibit this blockade of sodium channels and delayed conduction to a lesser degree. The most common side effects of the 5HT3 receptor antagonists are sedation, headache, dizziness, and anxiety.
Neurokinin (NK1) Antagonists A new area in antiemetic drug design is inhibition of substance P (neurokinin, NK1) receptors. Substance P mediates a number of biological effects including nausea, anxiety, pain, and vasodilation. It is found in areas of the brain that regulate emotion, in the spinal cord, and in endothelial cells in the small intestine. For sure there are substance P and NK1 receptors in the vomiting center. It’s a major neurotransmitter along with acetylcholine and serotonin. Aprepitant (Emend), an antiemetic, is the first of this kind of receptor antagonist to be approved for PONV. It also is used in prevention of nausea and vomiting from highly emetogenic cancer chemotherapy agents like cisplatin. Aprepitant is highly selective for the NK1 receptor and has no ability to block serotonin, cholinergic, dopamine, or steroid receptors. Yet, even with this high degree of selectivity, the drug has to be taken before nausea and vomiting begin. This drug is for prevention, not treatment, of nausea and vomiting. A single dose of 40 mg is given orally within 3 hours of induction. The drug is metabolized in the liver to several weakly active metabolites and excreted in the urine and feces. Side effects may include fatigue, dizziness, headache, constipation, and hiccups.
Miscellaneous Antagonists More recent evidence has shown that propofol (Diprivan) or dexamethasone (Decadron) is effective prophylaxis for PONV. Dexamethasone is a corticosteroid that is at least as effective as droperidol and the serotonin antagonists when used as a single agent early in the anesthesia regimen. It is given orally, 8 mg, within 2 hours of anesthesia and prevents PONV up to 72 hours. There do not appear to be significant side effects with its short-term use. It offers a replacement for droperidol when it comes to PONV prophylaxis, but it has no role in the treatment of established nausea and vomiting. The combination of a 5HT3 receptor antagonist and dexamethasone when used for prophylaxis has been reported to be 90 percent effective (PONV free). Dopamine (D2) receptor antagonists (promethazine and prochlorperazine), antihistamines (diphenhydramine, 260
dimenhydrinate), and anticholinergics (scopolamine, atropine) are inexpensive antiemetics used alone or in combination with the first-line drugs. These drugs act on multiple receptor types; antihistamines inhibit acetylcholine receptors in the vestibular center and histamine receptors in the area of the vomiting center. Promethazine and prochlorperazine are anticholinergic and antihistaminic as well. Acetylcholine is a chemical that nerves use to transmit messages to each other. Any anticholinergic character will interrupt the communication between the vomiting center and the CTZ. Scopolamine prevents communication between the nerves of the vestibule and the vomiting center in the brain by blocking the action of acetylcholine and acting directly on the vomiting center. Unfortunately, none of these drugs has the efficacy when used alone that the serotonin antagonists offer. Undesirable anticholinergic side effects such as dry mouth, confusion, constipation, and agitation often accompany these drugs. The concept of multimodal therapy for PONV used today relies on combination therapy (antiemetic drugs that have different mechanisms of action) such as dexamethasone plus a serotonin antagonist. Selection of total intravenous anesthesia, avoiding medications known to cause PONV (opioids, inhalational agents, nitrous oxide, reversal agents for muscle relaxants), or the use of regional anesthesia for pain control instead of general anesthesia is all part of the strategy.
Analgesics Alfentanil (Alfenta), fentanyl (Sublimze), sufentanil (Sufenta), and remifentanil (Ultiva) are all potent analgesics in the opioid family. Opioids are analgesics that produce pharmacologic effects similar to morphine by acting on one of three major endogenous opioid receptors, mu, kappa, or delta (see Chapter 19). These drugs are considered strong analgesics because they are able to suppress transmission of sensory information associated with moderate to severe pain of any origin. They depress transmission in the spinal cord by interacting with mu opioid receptors. These drugs are the analgesic component for monitored anesthesia care. Opioids are frequently used during MAC because they block pain associated with the procedure and/or condition undergoing surgery. These drugs are not anesthetics at any dose. Unlike midazolam and propol, opiates do not produce amnesia even at doses that create sedation. Sedation is more of a liability than a clinical benefit with opioid analgesics because the dose to produce sedation usually requires some degree of CNS and respiratory depression. For this reason, and because they produce nausea and vomiting, opioid analgesics are seldom used alone in MAC. When given IV or IM their onset of action is rapid. The duration of analgesia
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will depend on the characteristics of the specific drug. The more lipid-soluble opioid analgesics (alfentanil, fentanyl, sufentanil, and remifentanil) will undergo redistribution and may have a duration of about 1 hour or less. Additional drug administration or infusion can saturate tissues and prolong the recovery period with side effects. These drugs are CNS depressants and synergize with other depressant drugs. The most significant issue with these drugs is respiratory depression, especially if it continues in the postoperative period. In the event a patient is unresponsive to physical stimulation accompanied by shallow breathing (less than 8 breaths/minute) and has pinpoint pupils, as a result of overdose or unusual patient sensitivity to the opioid, there is a receptor-specific antagonist that may be used to reverse the respiratory depression. Naloxone (Narcan) is a pure opioid receptor antagonist used to reverse respiratory depression, sedation, and hypotension caused by opioid overdose. It does not stimulate the receptors; it does not produce any opioid response. In fact, in the absence of opioid-induced activity, naloxone does not exhibit any pharmacological response. It has to be used with caution in patients who are opioid dependent because it can precipitate withdrawal symptoms in these individuals. These opioid analgesics are used in the maintenance of anesthesia with the protocol of barbiturate and nitrous oxide/oxygen. They can be used as a continuous infusion with nitrous oxide/oxygen in the maintenance of general anesthesia. Ketorolac is a potent, parenterally active nonopioid analgesic (NSAID). It has been used both as an analgesic supplement to propofol sedation during local anesthesia and as an alternative to fentanyl for the treatment of intraoperative pain refractory to the administration of local anesthetic alone during MAC. A decided advantage of ketorolac over fentanyl is the absence of nausea and vomiting in the intraoperative and postoperative periods. However, ketorolac has a number of serious effects for consideration before it can be used. It is contraindicated in patients with a history of or active peptic ulcer disease or GI bleeding because it inhibits platelet function. It cannot be used in patients at risk for renal failure or in surgeries where there is an increased risk of bleeding.
Muscle Relaxation Most general anesthetics that take patients into Stage III, Plane 3 anesthesia produce skeletal muscle relaxation. However, it may be advantageous in certain operations (abdominal and thoracic) to have skeletal muscle relaxation for a long time with minimal CNS depression. For this purpose, neuromuscular blocking drugs, also called paralytics, such as succinylcholine, may be administered during
surgery. These drugs produce adequate skeletal muscle relaxation by interfering with acetylcholine-modulated nerve conduction at the synaptic site while patients are maintained in early Stage III anesthesia. The neuromuscular blocking drug succinylcholine is a standard for rapid sequence induction (RSI) used briefly at the beginning of some procedures to facilitate endotracheal intubation. Succinylcholine is the only depolarizing agent used for RSI. Because of its rapid onset, ultrashort duration of action, and safety, it is the paralytic of choice in almost all cases of RSI in adults. For more detail on succinylcholine and other muscle relaxants, see Chapter 8.
Antisecretory/Antispasm Anticholinergic drugs may be used as preanesthetic medications to prevent the increase in salivary and bronchial secretions induced by some anesthetics. Bronchial secretions of mucus usually line the respiratory tract and may impair the transfer of oxygen and anesthetic across the lungs. If the secretions are not controlled, hypoxia may develop. LO 18.7
SPECIAL CONSIDERATIONS AND CAUTIONS Many patients are not aware of possible allergies or hypersensitivities that they have. This lack of awareness is especially likely if patients have not previously encountered surgery or preanesthetic medications. Therefore, patients should be carefully observed for any unusual reactions to medications before and after general anesthesia. Anaphylactoid reactions are rare with anesthetics. Special Type II hepatitis associated with volatile liquid anesthetics has been described. It is more usual that the patient may experience itching and redness due to histamine release (barbiturates, etomidate); this is not an allergic reaction. Vital signs should be monitored frequently before, during, and after anesthesia. During the postoperative recovery period, patients’ airways must be kept unobstructed. It is important to check patients for signs of hypoxia (skin discoloration), laryngospasm, or gagging, which can precipitate aspiration of fluid into a patient’s lungs. Patients should be positioned so that the potential for aspiration of secretions is minimized. Intravenous fluids and vasopressor drugs should be kept available for the treatment of hypotensive episodes. Patients should be monitored and positioned to avoid redistribution of anesthetic to the CNS, which may precipitate severe hypotension and respiratory arrest during the recovery period. Most of the problems that arise following general anesthesia result from residual depression of the CNS. Patients frequently feel “hung over,” dizzy, or nauseous, and Chapter 18 • General Anesthetics
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should be assisted, since mental disorientation may lead to impaired judgment and incoordination. Three drugs in this chapter—methohexital, midazolam, and droperidol— have a special cautionary instruction for their use, called a black box warning. The recommendation that patients be fully monitored, electronically and by third-party observation (not the attending physician or surgeon), is identified for methohexital and midazolam because of the potential to cause respiratory and cardiac depression. Close attention to monitoring patient signs should be the standard of care with the use of all anesthetics. Postanesthetic medications such as analgesics, muscle relaxants, and tranquilizers will potentiate the residual CNS depression of general anesthetics. Antibiotics such as streptomycin, kanamycin, and erythromycin will potentiate the skeletal muscle relaxation to produce muscle weakness and fatigue. Because propofol is an emulsion, it should be used with caution in patients with lipid metabolism disorders such as primary hyperlipoproteinemia, diabetic hyperlipidemia, and pancreatitis. Elevations in serum triglycerides may occur when it is administered for extended periods of time. Patients at risk of hyperlipidemia should be monitored for increases in serum triglycerides or serum turbidity. The drug is contraindicated in patients with a known hypersensitivity to propofol or its components. Several of the inhalation anesthetics and surgical adjuncts (skeletal muscle relaxants) produce malignant hyperthermia in certain individuals. The intravenous anesthetics do not cause malignant hyperthermia. This acute toxicity is due to a genetic defect. Malignant hyperthermia is associated with a drastic increase in body temperature, acidosis, electrolyte imbalance, and shock. The mechanism by which hyperthermia occurs is believed to be related to the anesthetic-induced potentiation of calcium hyperreactivity in susceptible individuals. The hyperactive biochemical reactions progress so quickly that treatment must be started immediately to reduce the risk of death. Treatment of hyperthermia includes reducing body temperature with ice packs and controlling arrhythmias and acidosis with appropriate drugs. Unfortunately, the incidence of fatality in malignant hyperthermia is high. Prevention is primarily directed at obtaining a good family history about other episodes of difficulty during operative procedures. Dantrolene is the drug of choice in managing the sequelae of malignant hyperthermia.
Solution Incompatibilities The injectable anesthetics, as their name implies, must be prepared as solutions to facilitate parenteral administration. Frequently, parenteral medications are given in combination for convenience and efficient drug handling and to minimize patient discomfort by reducing the number 262
of injections. Considering the variety of drugs that may be used during an operation, it is understandable why combining medications might be useful. Drug admixture may be performed by adding solutions to an existing intravenous line or by mixing two or more drugs in the same syringe prior to injection. Note: Not all drugs can be mixed in the same syringe without compromising the activity of the active components. Some drug combinations result in discoloration of the solution, haze formation, or even precipitation. These are signs of drug incompatibility that should alert medical personnel to discard the solution and avoid such combinations in the future. Neither the fentanyl-droperidol combination product nor ketamine should be combined in the same syringe with a barbiturate because drug precipitation results. Methohexital and thiopental have been reported to be incompatible with several antibiotics, antihistaminics, and opioid analgesics. Examples of drugs that should not be combined with the barbiturate anesthetics are chlorpromazine, kanamycin, lidocaine, promazine, streptomycin, tetracycline, methyldopa, and prochlorperazine. Thiopental should not
Note to the Health Care Professional In an ambulatory surgical setting, patients must be monitored through the recovery period. Because of the depressant nature of anesthetics, especially causing residual mental confusion, and the potential for adverse effects to occur with any anesthetic, patients should be alerted to the “Do’s and Don’ts” after anesthesia. • Don’t rely on memory for spoken instructions (written instructions should be given to the patient in addition to spoken instructions). • Do leave the health care facility accompanied by a responsible adult. • Don’t operate complex equipment for at least 24 hours (someone else should be driving the patient home). • Don’t make any important decisions or sign any legal documents for the day. • Don’t take any medications unless prescribed by or discussed with the patient’s physician. • Don’t drink alcohol for at least 24 hours. • Do remain quietly at home for the day and rest. • Do arrange for someone to take care of any small children for the day. • Do take liquids first and slowly progress to a light meal. • Do call the designated medical professional, nurse anesthetist or physician, or the surgery center if any questions arise.
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be combined with amikacin, codeine, meperidine, morphine, penicillin G, promethazine, succinylcholine, and tetracycline because precipitation will occur. Solutions containing barbiturates are usually alkaline (pH greater than 10). As a rule, these alkaline solutions should not be mixed with acid solutions because the barbiturate will precipitate. Such incompatible acid solutions include atropine, scopolamine, and succinylcholine. Methohexital undergoes a specific interaction with silicone and rubber, which dictates that it should never be in contact with rubber stoppers or parts of syringes that have been treated with silicone. Propofol should not be used if there is evidence of separation of the emulsion phases. Unused portions of propofol or solutions containing propofol at the end of the anesthetic procedure or by 6 hours, for longer procedures/ICU use, should be discarded. LO 18.8
PREFERRED USE OF ANESTHETICS The volatile anesthetics are used for maintenance anesthesia in an operating room. They are easy to administer, have the benefit of additional skeletal muscle relaxation, and can be controlled by the anesthesiologist as needed to keep the patient oxygenated and away from medullary
depression. The frequently used inhalational agents are nitrous oxide, enflurane, sevoflurane, and isoflurane. Sevoflurane is an anesthetic of choice for induction or maintenance anesthesia in inpatient and outpatient procedures because of its minimal respiratory effects. For most procedures, surgical or diagnostic, it’s standard practice to begin with an intravenous agent, either to calm the patient or to make a smooth transition to another maintenance anesthetic. Propofol is the most frequently used induction anesthetic today. It is used with confidence in the operating room and ambulatory surgical centers. It is a preferred anesthetic among the drugs used for balanced anesthesia and as a maintenance anesthetic. It has frequently replaced barbiturates as a sedative-hypnotic. Propofol is an anesthetic of choice for procedures requiring conscious sedation and continuous sedation of mechanically ventilated patients in the intensive care (ICU) setting. Its profile—no nausea and vomiting, no tissue accumulation or neuromuscular blocker potentiation—makes for a reliable, uncomplicated, and satisfactory recovery period. For Monitored Anesthetic Care, the most frequently used drugs include midazolam, propofol, ketamine, fentanyl, alfentinil, and lidocaine. Depending on the type of procedure, another anesthetic also may be added.
Patient Administration and Monitoring Patients are usually exposed to these drugs in an operating room environment. For such procedures it is expected that the patient will be closely monitored during and after surgery to ensure adverse reactions are minimized. Even for diagnostic procedures, the patient is kept for observation until it is clear there is no immediate risk. The opportunity for adverse effects is more likely to occur when information on patient medical history is inadequate prior to the selection of the anesthetics and premedication regimen. Patient history is extremely important to ascertain which drugs are most appropriate. Patient interview will provide information that is critical to minimizing adverse reactions to anesthetics. Go to www.anesthesiapatientsafety.com and select “About Anesthesia” in the left side panel. Click on “Preanesthetic Questionnaire” for an excellent sample of what may be covered during a patient history. Alcohol consumption, blood pressure medication, antibiotic, and OTC product use should be thoroughly reviewed. Intravenous anesthetics will be potentiated by CNS depressants, including alcohol in cough/cold preparations.
Hypersensitivity to anesthetics and/or premedications from previous exposure, or knowledge of a family member experiencing difficulty during surgery, may provide evidence of a contraindication to specific anesthetics. This is especially valuable as an indication of predisposition to malignant hyperthermia.
Use in Pregnancy Midazolam is Food and Drug Administration (FDA) Pregnancy Category D because an increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) has been suggested in several studies. Patients should be apprised of the potential hazard to the fetus if this drug is used for more than a single exposure during pregnancy. Single exposure as an adjunct to anesthesia is less likely to be an issue when administration is warranted during pregnancy. Other general anesthetics are classified as having been designated FDA Pregnancy Category B or C.
Midazolam is contraindicated in patients with acute narrowangle glaucoma, although it may be used in open-angle glaucoma.
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Chapter Review Understanding Terminology Answer the following questions. 1. Name the brain center that influences mood, motivation, and the perception of pain. (LO 18.1) 2. Differentiate among analgesia, general anesthesia, dissociative anesthesia, medullary depression, and medullary paralysis. (LO 18.1) 3. Explain the difference between induction of anesthesia and maintenance of anesthesia. (LO 18.1, 18.2) 4. Explain the concept of balanced anesthesia. (LO 18.1) 5. Explain when propofol is a preferred anesthetic. (LO 18.8)
Acquiring Knowledge Answer the following questions. 1. How does general anesthesia differ from sleep? (LO 18.1) 2. How is general anesthesia produced? (LO 18.1) 3. How do the effects of general anesthetics on the CNS differ from those of lesser anesthetics? (LO 18.1, 18.4, 18.5) 4. What do the various stages of anesthesia represent? (LO 18.1) 5. What effects do general anesthetics have on the cardiovascular and respiratory systems? (LO 18.1, 18.5) 6. How may the general anesthetics produce skeletal muscle relaxation? (LO 18.4) 7. How do the inhalation anesthetics differ from the injectable anesthetics? (LO 18.2, 18.4, 18.5) 8. What is neuroleptanesthesia? (LO 18.2) 9. For what purpose are the various adjunct medications administered? (LO 18.5) 10. What types of drug interactions may occur in postsurgical patients? (LO 18.6, 18.7)
Multiple Choice Use your critical-thinking skills to answer the following questions. 1. Which of the following anesthetics exhibits potent analgesic properties? (LO 18.1) A. lidocaine B. halothane C. ketamine D. nitrous oxide and ketamine 2. What is the best reason for using a balanced anesthesia strategy? (LO 18.1, 18.7) A. producing complementary effects using a few drugs avoids unnecessary intense (deep) CNS depression with one anesthetic to achieve the same effect B. the concentration of volatile anesthetic in the alveoli is balanced against the amount of anesthetic in the blood C. less monitoring of anesthesia is required D. fewer patients experience emergence delirium 3. Why is propofol a drug of choice for induction and maintenance of anesthesia? (LO 18.2, 18.8) A. it is a potent analgesic at all doses B. it slowly brings the patient to the stage of surgical anesthesia C. it is a complete anesthetic with a quick onset of action and recovery period uncomplicated by nausea and vomiting D. it is administered by special vaporizer to avoid mask delivery
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4. Which of the following drugs is associated with its correct pharmacological effect? (LO 18.6, 18.7) A. ketamine: nausea B. sevoflurane: skeletal muscle relaxation C. methohexital: hallucinations and colorful dreams D. etomidate: hepatitis 5. Which of the following is true about laryngospasms? (LO 18.7) A. they rarely occur because volatile anesthetics depress the CNS B. they involve stimulation of the bronchiolar smooth muscle C. drug-induced increased salivary secretion can trigger them in pediatric patients D. they can be avoided by using a volatile anesthetic with ketamine 6. Which of the following drugs is matched correctly with its use or action? (LO 18.1, 18.4) A. chlorpropamide: induction anesthesia B. ondansetron: maintenance anesthesia C. droperidol: maintenance anesthesia D. ketamine: dissociative anesthesia 7. Which of the following is not correct? (LO 18.3) A. ketamine causes chloride ions to flow out of the nerve cell by binding to GABA B. propofol binds to the GABAA receptor and enhances hyperpolarization of the neuron C. barbiturates and propofol act on the receptor and directly on the chloride channel D. potent anesthetics enhance GABAA and glycine receptors 8. The major routes that remove etomidate and midazolam from the body are which of the following? (LO 18.3, 18.5) A. hepatic metabolism and renal excretion B. excretion through the lungs and sweating C. accumulation in fat tissue and redistribution D. increased salivation and bile production
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Select the types of anesthesia in which there is a loss of consciousness. (LO 18.1) A. local anesthesia B. Monitored Anesthesia Care C. general anesthesia D. balanced anesthesia 2. Choose the different classes of general anesthetics. (LO 18.2) A. injected B. inhaled C. oral D. topical 3. Which of the following is a route of excretion for volatile liquid anesthetics? (LO 18.5) A. renal B. GI tract C. exhalation D. sweating Chapter 18 • Chapter Review
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Chapter Review Continued 4. Select the mechanisms by which anesthetics inhibit CNS activity. (LO 18.3) A. bind to GABA receptors B. Cl− ions move across membrane C. membrane is depolarized D. ion channels open 5. Which drugs would be used as adjunct therapy to anesthesia during surgery? (LO 18.6) A. analgesics B. antiarrhythmics C. antianxiety D. anticholinergics
Sequencing Place the following stages of anesthesia in order from first symptoms experienced to last. (LO 18.1) __________________
__________________
__________________
First
__________________ Last
medullary paralysis analgesia excitement surgical anesthesia
Classification Place each indication under the appropriate stage of anesthesia. (LO 18.1) elevated blood pressure
respiratory paralysis
circulatory collapse
return to normal heart functions
giddiness
euphoria
skeletal muscle relaxation
elevated heart rate
Stage I
Stage II
Stage III
Stage IV
Matching Match the following drugs with the type of anesthesia for which they are preferred; each classification may be used more than once (LO 18.2, 18.8) a. maintenance anesthesia b. induction anesthesia c. monitored anesthesia 1. 2. 3. 4.
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_____ _____ _____ _____
ketamine nitrous oxide midazolam propofol
5. _____ sevoflurane 6. _____ fentanyl 7. _____ enflurane
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Documentation Using the doctor’s notes below, answer the following questions. (LO 18.2) One dose of Ketamine administered at 08:00 Procedure begun at 08:15 Procedure should take 30 minutes to complete. a. What type of anesthetic is ketamine? b. Should the doctor have started the procedure earlier or later, or was this an appropriate amount of time to wait before starting? c. What is the normal duration of action of ketamine? Will another dose be needed? d. For what type of side effects should the patient be monitored?
Labeling Fill in the missing labels. (LO 18.1)
Stage I Analgesia
Cerebral cortex
Stage II Excitement (delirium)
Stage III Surgical anesthesia plane 1 plane 2 plane 3
Hypothalamus Thalamus
plane 4 Stage IV Medullary paralysis
Medulla Oblongata
For interactive animations, videos, and assessment, visit:
www.mcgrawhillconnect.com Chapter 18 • Chapter Review
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Chapter 19
O pioid A nalgesics DRUG CLASS AT A GLANCE OTC Cough-cold
YES
PRESCRIPTION
YES
YES SCHEDULED DRUGS Analgesics CII, CIII, CIV dextromethorphan is exempt FDA PREGNANCY CATEGORY
B, C, D
INDICATIONS Moderate to Severe Pain, pre/post-op medication, cough suppression
KEY TERMS addiction: a chronic neurobiologic disease in which genetic, psychosocial, and environmental factors induce changes in the individual’s behavior to compulsively use drugs despite the harm that may result. agonist: drug that attaches to a receptor and initiates an action. analgesia: relief from pain. analgesic: substance (synthetic or naturally occurring) that inhibits the body’s reaction to painful stimuli or perception of pain. antagonist: drug that attaches to a receptor, does not initiate an action, but blocks an agonist from producing an effect. antidiuretic hormone (ADH): substance produced in the hypothalamus and secreted by the pituitary gland that modulates urine production and allows the kidneys to reabsorb water in order to conserve body water. antitussive: a drug that suppresses coughing. anuria: condition in which no urine is produced. dysphoria: feeling of discomfort or unpleasantness. emesis: vomiting. endogenous: naturally occurring within the body.
endorphins: neuropeptides produced within the CNS that interact with opioid receptors to produce analgesia. expectorant: substance that causes the removal (expulsion) of mucous secretions from the respiratory system. hyperalgesia: an abnormally painful response to a stimulus. neuropathic pain: pain resulting from a damaged nervous system or damaged nerve cells. nociceptor: specialized peripheral nerve cells sensitive to tissue injury that transmit pain signals to the brain for interpretation of pain. nonopioid analgesic: formerly known as nonnarcotic analgesics, such as NSAIDs and COX-2 inhibitors. oliguria: condition in which very small amounts of urine are produced.
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opiate: drug derived from opium and producing the same pharmacological effects as opium. opioid: drug that produces the same pharmacological effects as opium and its family of drugs or the neuropeptides (enkephalin, endorphin) produced by the body. opioid analgesics: chemically related to morphine or opium and used to relieve pain. opioid antagonist: a drug that attaches to opioid receptors and displaces the opioid analgesic or opioid neuropeptide. peripheral nerve: part of the nervous system that is outside the central nervous system (the brain or spinal cord), usually near the surface of the tissue fibers or skin. phlegm: secretion from the respiratory tract; usually called mucus. physical dependence: condition in which the body requires a substance (drug) not normally found in the body in order to avoid symptoms associated with withdrawal, or the abstinence syndrome. referred pain: origin of the pain is in a different location than where the individual feels the pain. spasmogenic: causing a muscle to contract intermittently, resulting in a state of spasms. synthetic drug: drug produced by a chemical process outside the body. tolerance: ability of the body to alter its response (to adapt) to drug effects so that the effects are minimized over time.
Learning Outcomes
After studying this chapter, you should be able to
19.5 list the adverse effects of these drugs.
19.1 explain the pathway for pain recognition and how opioids produce analgesia.
19.7 discuss the actions of opioid antagonists.
19.2 describe the sources of opioid analgesics. 19.3 discuss the pharmacological effects of these drugs.
19.6 explain acute opioid poisoning.
19.8 list drug interactions. 19.9 discuss the specific terms associated with pain, analgesia, addiction, cough, and opioid receptors.
19.4 discuss administration, absorption, and metabolism of these drugs.
Introduction
Pain functions primarily as a protective signal. Pain may warn of imminent danger (fire) or the presence of internal disease (appendicitis or tumors). On the other hand, pain may be part of the normal healing process (inflammation). Relief from pain is desirable when the duration and intensity of pain alter the ability of an individual to function efficiently. In such situations, analgesic drugs are useful because these agents relieve pain without producing a loss of consciousness. There are two major classes of analgesics: the opioid analgesics and the nonopioid analgesics. Opioid analgesics are usually referred to as strong analgesics, whereas nonopioid drugs are considered mild analgesics. This classification suggests the type of pain that can be alleviated by each group. Opioid analgesics are capable of inhibiting pain of any origin. However, these drugs are used primarily to relieve moderate to severe pain of trauma, pain associated with myocardial infarction, pain associated with terminal illness, and postoperative pain.
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LO 19.1 1
intensity of the pain by increasing the frequency of signals sent to the spinal cord and then to specialized areas within the CNS (Figure 19.1). The signals travel through the spinal cord into the area called the dorsal horn, where they are routed to the appropriate area of the brain that can interpret the intensity and quality of pain present. Pain signals arrive in the spinal cord through A-delta nociceptor and C-nociceptor fibers. The continuing signal is transmitted in the ascending pathways to the brain. If the originating (point-of-injury) signal is transmitted through the A-delta fibers (myelinated), the pain is consciously experienced as sharp. If the signal is passed through C fibers (unmyelinated), dull, aching pain is felt. Nociceptive pain can only occur when all neural equipment (nerve cells, nerve endings, spinal cord, and brain) is working properly. When pain results from abnormal signals or nerves damaged by entrapment, infection (herpes zoster or HIV), amputation, or diabetes, it is called neuropathic pain.
LO 19.9
PAIN The sensation of pain is comprised of at least two elements: the local irritation (stimulation of peripheral nerves) and the recognition of pain (within the CNS). Free nerve endings called nociceptors are located in the skin, muscle, joints, bones, and viscera. Nociceptors respond to tissue injury and painful stimuli. When there is no injury, there is no pain stimulus, so the nociceptors are quiet. When a pain-generating event happens, biochemical changes occur within the localized area of the injury. Usually, prostaglandins, histamine, bradykinins, serotonin, and Substance P are among the peripheral neurotransmitters released that trigger nociceptors. Substance P is a neuropeptide released from specific sensory nerves in the brain and spinal cord. It is associated with inflammation and pain. In nociception, Substance P transmits information about tissue injury at the peripheral receptors to the CNS, where the sensation of pain is recognized. Nociceptors alert the brain to the
Figure 19.1
Pathways for Pain and Sites of Drug Action for Pain Relief Primary somesthetic cortex Somesthetic association area
Areas of pain perception
Opioid analgesics Thalamus
Hypothalamus and limbic system
Reticular formation
Local anesthetics p Spinothalamic tract Opioid analgesics
Spinoreticular tract
Nerve fiber
Nonsteroidal (nonopioid) antiinflammatory drugs Local anesthetics
Nociceptor
Spinal cord Anterolateral system
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Pain duration is either acute or chronic. Acute pain usually appears in association with an observable injury (e.g., sunburn, broken foot, muscle sprain, or headache) and disappears when the injury heals. Chronic pain persists for weeks, months, or years even with analgesic therapy. Nociceptive pain can be either acute or chronic. Neuropathic pain is chronic, even though it may be intermittent. If an injury doesn’t heal or the pain is not adequately inhibited, nociceptors get “really irritated,” a condition known as peripheral sensitization, and send so many signals through the CNS that the patient overresponds to even normal stimuli, such as a feather or brush touched to the area. In neuropathic conditions sensitization also can occur within the spinal neurons observed as overresponsiveness (hyperalgesia), prolonged pain, or the spread of pain to an uninjured area (referred pain). No matter what type of pain is present, relief from pain (analgesia) is the therapeutic goal. The specialized medical discipline of pain management has changed the spectrum of therapy and the types of drugs used, especially to achieve satisfactory analgesia as soon as possible. Inadequate control of pain can delay healing. With chronic pain, psychological and emotional changes occur that cause the patient to become tired and irritable; patients develop insomnia, significant stress responses such as increased heart rate and blood pressure, depression, impaired resistance to infection, and even increased sensitization to pain. The psychological component associated with the inability to permanently relieve the pain intensifies the response to pain by stimulating the CNS. Pain management and selection of the most appropriate analgesic depend on the type and duration of pain present. In other chapters, pain relief (analgesia) has been shown to be the primary therapeutic action of local anesthetics and nonsteroidal antiinflammatory drugs (NSAIDs). By inhibiting sodium and potassium ion movement through the nerves, local anesthetics block nerve conduction and the sensation of pain is avoided (Chapter 10). Analgesia also is produced by interrupting the metabolic pathway of inflammation, such as inhibition of prostaglandins by NSAIDs (Chapter 20). Local anesthetics and NSAIDs act at the site of injury or at the level of the peripheral nerves (Figure 19.1). Because some antiepileptic drugs and tricyclic antidepressants depress neuronal excitability and suppress abnormal discharges, these drugs also play an important adjunct role in pain management. Even though local anesthetics and antiepiletic drugs are used to reduce or ameliorate pain, the NSAIDs, acetaminophen, and COX-2 inhibitor drugs are most often referred to as the nonopioid analgesics. The nonopioid analgesics are discussed in the following chapter.
Although the terminology used to describe the mechanism of analgesia is relatively new, the drugs discussed in this chapter, opioid analgesics, in their natural plant form, have been medicinally used for 5000 years. LO O 19.1 1
LO O 19.2 2
LO O 19.3
LO 19.5 5
LO 19.7 7
LO 19.9
O PIOID A NALGESICS Clinical Indications Opioid analgesics are first-line therapy for pain associated with procedures (bone marrow biopsy), pain due to trauma (burns, vehicular accident), cancer, or visceral pain (pancreatitis, appendicitis). It is held that opioid analgesics can relieve virtually any type of pain. Certainly, all opioid analgesics relieve moderate to severe acute and chronic pain. Such pain is often associated with myocardial infarction, post-trauma injury, and cancer. Occasionally the root cause of chronic pain remains unidentified. Opioid analgesics are the drug of choice in treating acute postoperative pain, including dental pain (oral analgesia), because there is no increased risk of bleeding (as with NSAIDs). The majority of the opioid analgesics are used for the relief of acute and chronic pain. A few, such as fentanyl (Sublimaze, Duragesic), alfentanil (Alfenta), and sufentanil (Sufenta), are primarily indicated for preoperative sedation to reduce patient apprehension. In making the patient less apprehensive, physiological mechanisms are no longer poised to fight the anesthesia. As a result, premedication with opioids often reduces the amount of anesthetic required and facilitates induction of anesthesia. Other opioids, such as codeine, hydrocodone, and dextromethorphan, are widely used to suppress coughing, while difenoxen/atropine (Motofen) and loperamide (Immodium) are the active agents in antidiarrheal medications. The antitussive opioids are presented at the end of this chapter. The antidiarrheal opioids are presented in Chapter 34 with other drugs that affect GI motility.
Source of Opioids Until recently, drugs that were extracted from opium (opiates) or synthetic chemicals that produced the same pharmacological effects as opium were called narcotic analgesics. While this name still applies to the laws that govern the use of this class of drugs, current medical and research terminology refers to these drugs as opioid analgesics. The naturally occurring opiates (derivatives of opium) include morphine and codeine. Morphine is the largest component of the chemicals (alkaloids) extracted from the poppy plant. The term opioids is used Chapter 19 • Opioid Analgesics
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today for any molecule, whether natural or synthetic, that acts on opioid receptors. Morphine is the prototype or standard opioid analgesic. Because it has been used for centuries as a medicinal drug, its clinical effects are well established and its dose-response has been well documented. This allows morphine to be the standard by which the potency of all the other opioid analgesics is measured. The opioids vary in their potency, onset of action, and incidence of opioid side effects ( Table 19:1). Tolerance and physical dependence are factors that influence opioid use. Tolerance (decreasing effects) develops to all opioids. When tolerance develops to the annoying side effects of the drug (sedation), it is
considered a therapeutic benefit. However, when tolerance results in the need for a larger dose of drug to produce a CNS action (euphoria, analgesia), that is not a beneficial outcome. In fact, more drug to reach a state of good feeling may reinforce behavior in certain individuals associated with abuse or addiction. Physical dependence develops with long-term daily use of all strong opioids. Because of the potential for abuse, opioid analgesics are federally restricted (controlled) substances. These drugs can be obtained only by prescription from a physician registered and licensed with the Drug Enforcement Agency (DEA). This status obligates strict maintenance
Table 19:1
Pharmacological Effects of Opioid Analgesics Drug
Alfentanil
Addiction potential *
Analgesic potency
Antitussive activity**
Incidence of nausea and vomiting**
Respiratory depression**
Same as morphine
*
*
*
Codeine
Low
Less than morphine
3
1
1
Heroin
Highest
Greater than morphine
?
1
2
Hydrocodone
Low
Less than morphine
3
?
1
Hydromorphone
High
Greater than morphine
3
1
2
Levorphanol
High
Same as morphine
2
1
2
Meperidine
High
Same as morphine
1
2
2
Methadone
Low
Same as morphine
2
1
2
Morphine
High
Good
3
2
2
Oxycodone
High
Same as morphine
3
2
2
Oxymorphone
Highest
Greater than morphine
1
3
3
Pentazocine
Moderate
Less than morphine
*
2
2
Propoxyphene
Low
Less than morphine
*
1
1
Greater than morphine
*
*
*
Sufentanil
*
*Not rated. **3 = high; 2 = moderate; 1 = low.
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of records and specific procedures for secure storage of the drugs. Because of their high abuse potential, most opioids used as analgesics or adjuncts to anesthesia are restricted to Schedule II. Schedule II (CII) requires that listed drugs must have a new prescription written for each refill. In the late nineteenth century, morphine was chemically converted into heroin under the good intention of producing an analgesic that was less addicting than morphine. Unfortunately, heroin is three times more potent than morphine and more rapidly addicting. Heroin is fully restricted to Schedule I (CI) because it has a high abuse potential and no medically sanctioned use in the United States. This means it cannot be legally prescribed in the United States. Opioids with less abuse potential, such as codeine, appear in Schedules III and V according to the strength (amount of codeine) of the preparation. Opioids with the least abuse potential such as opiates used as antidiarrheals are Schedule V drugs. Select opioid analgesics—codeine, dextromethorphan,and hydrocodone—are approved for use alone or in combinations to suppress coughing. Dextromethorphan does not require a prescription for cough preparation sold over-the-counter, but hydrocodone, under Schedule III, does. Dextromethorphan is under a great deal of scrutiny because of the misuse and abuse of OTC products by minors. Efforts to restrict access and/or sale to individuals under 18 years of age are ongoing. The classification schedules (CI to CV) associated with various opioid controlled substances are indicated in Table 19:2 along with the usual adult doses for analgesia. Codeine, especially, is in combination products for the treatment of cough and cold symptoms. This is presented in Table 19:4 under the Antitussive section.
Site and Mechanism of Action Pain recognition involves a component that intensifies the response to pain because the CNS anticipates how painful the injury will be or how the continuing chronic pain will feel. This recognition leads to anxiety and apprehension (CNS stimulation), which heightens the reaction to pain. Opioid analgesics are called central analgesics because they selectively act within the CNS to reduce the reaction to pain. Opioid analgesics do not impair the function of peripheral nerves. The pain is still present (especially in chronic conditions), but patients respond differently than before as though they can tolerate the pain. Several different types of opioid receptors have now been identified within the spinal cord and brain. Morphine was thought to interact with membrane-bound receptors as long as 50 years ago. However, it wasn’t until the 1970s that evidence for an opioid receptor in
the body was confirmed by the discovery of the endogenous peptides. These peptides include endorphin, enkephlin, dynorphin, and the newest ones, nociceptin and nocistatin. The word endorphin is derived from the words endogenous and morphine. These peptides are believed to be important for survival because, when released, they provide pain relief that allows the injured person to move away from the harmful stimulus. Endorphins have been shown to be more than four times more potent than intravenous morphine. Eventually, the peptides are metabolized, levels decrease, and the pain signal returns, causing the person to seek help to reduce the continuing pain. Three opioid receptors are the most clinically important—mu, kappa, and delta. These receptors are G-protein receptors. There are two types of mu receptors. Mu1, located outside the spinal cord (CNS), “interprets pain.” Mu2, found throughout the CNS, is responsible for respiratory depression, analgesia, euphoria, and physical dependence. Each of the endogenous opioid peptides has a preference for one of the opioid receptors, although they may interact with multiple receptors. Endorphins are produced within the pituitary and hypothalamus and are selective for mu receptors. Enkephlins, produced throughout the CNS and peripheral nerve endings, prefer delta receptors, while dynorphins, primarily found in pain nerve endings, interact with kappa receptors. Reduction in the awareness and reaction to pain is controlled through a combination of mu, kappa, and delta receptors within the brain. Morphine and the other opioid analgesics act by binding to opioid receptors and mimicking (agonist) the effects of the analgesic peptides. The therapeutically important opioid analgesics interact with mu and kappa receptors. These drugs inhibit neurotransmitter release such as Subtance P, inhibit nociceptor signals from reaching the spinal cord, reduce nerve excitability, and alter pain perception (see Figure 19.2). Opioid analgesics reduce pain by more than one action. When opioids bind to their G-protein (mu) receptors, calcium ion channels on presynaptic neurons close. Calcium ions cannot flow into the cells and facilitate neurotransmitter release such as acetylcholine, Substance P, catecholamines, and glutamate. Glutamate is an excitatory neurotransmitter that sends the pain signal along the nerve. So opioids prevent pain transmission when glutamate release is inhibited. Next, opioids bind to the postsynaptic mu receptors and open potassium ion channels. Potassium ions move out of the cell, producing a hyperpolarized state in which the nerve cannot respond to pain signals so further transmission to the brain is interrupted. Opioids interact with their receptors at different CNS levels. Chapter 19 • Opioid Analgesics
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Table 19:2
Analgesic Doses of Centrally Acting Analgesics Schedule
Adult dose analgesia
Intramuscular onset (min)
Administration duration (hr)
Codeine
II
15–60 mg PO, SC, IM, IV*
15–30
4–6
Hydromorphone (Dilaudid) Hydromorphone ER (Exalgo)
II II
2 mg PO, 1–2 mg SC, IM, IV* 8–64 mg PO QD
15–30 —
4–5 24
Opium tincture
II
0–6 ml QID
—
—
Drug (Trade Name) Opiates
Heroin
Morphine
Oxycodone (Roxicodone)
I
II
II
No recognized medicinal value in the United States 5–20 mg IM, SC**
15–20
3–7
5 mg PO*
15–30
4–6
II
8–75 mcg /Kg IV
—
30–60
Butorphanol***
III
0.5–2 mg IM**, IV
10
Fentanyl (Sublimaze)
II
Oxymorphone (Numorphan)
Opioids
Alfentanil (Alfenta)
Buprenorphine (Buprenex)*** (Suboxone)***
II
III IV
Butorphanol nasal spray
II
Fentanyl transdermal (Duragesia-12, 25)
II
Fentanyl transmucosal (Actia, Fentora, Onsolis)
1–1.5 mg IM, SC*; 0.5 mg IV
5–10
3–6
— —
— 4–8
0.05–0.1 mg/kg IM
—
5–15
3
200–1800 mcg lozenge on a stick; buccal tablets 200–800 mcg or film 200–1200 mcg
—
1.5
2–3 mg PO, SC
30–90
6–8
0.3 mg (1 ml) deep IM or slow IV 12–16 mg maintenance dose PO 1 mg (1 spray in one nostril); repeat if needed in 90 min Individualized dose
3–4
1–2
Levorphanol (Levo-dromoran)
II
Methadone (Dolophine, Methadone)
II
2.5–10 mg PO, IM, SC**
10–15
4–6
II
10–30 mg PO* Immediate release tablets 5 mg *
— —
— —
Meperidine (Demerol )
II
Nalbuphine (Nubain)***
***
Pentazocine (Talwin)***
IV
Remifentanil (Ultiva)
II
Oxycodone (Oxycontin)
Propoxyphene (Darvon, Dolene) Sufentanil (Sufenta)
50–150 mg PO, SC, IM**
10 mg/70 kg SC, IM, IV*
50–100 mg PO; 30 mg IM, SC**
15
2–4
3–6
20
3
IV
65 mg PO**
15–30
II
8–30 mcg/kg IV
—
1.5
50–100 mgPO*
15–30
2–4
Continuous infusion
Central analgesic (Nonopioid receptor active) Tramadol (Ultram)
10–15
4–6
*Dose repeated every 6 hours. **Dose repeated every 3–4 hours. ***These drugs are partial agonist analgesics. Nalbuphine is not a scheduled controlled substance.
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Figure 19.2
Sites of Opioid Receptor Interaction to Produce Analgesia
2 3
Nerve fiber
1 1 Nociceptor
Spinal cord (a) 1 Peripheral nociceptors, 2 Presynapse, and 3 Postsynapse correspond to the same areas in part (b) Dorsal horn spinal cord Ca2⫹ Opens potassium ion channel, promotes outflow
3
2 ⴙ
K⫹
ⴚ
Stops calcium ion inflow so glutamate and Substance P cannot be released
MOR ⴚ
MOR
1 ⴚ
Pain stimulus
AMPA NMDA
K⫹
Glutamate Substance P NK1 Secondary afferent neuron
Primary afferent fiber
Periphery
(b) Activity at the mu receptors (a) Location of opioid receptor activity. (b) Mu receptors (MOR) in the periphery (1) and presynaptic (2) neurons of the dorsal horn inhibit pain signals (nerve transmission) by decreasing calcium movement into the cell. In the postsynaptic (3) neurons of the spinal cord, mu receptors open potassium channels (outflow of potassium ions) resulting in hyperpolarization so the nerve cannot respond to additional pain signals.
All of these agonist actions contribute to pain relief. Most of the traditional opioids (morphine, oxymorphone, oxycodone, methadone, fentanyl) are pure agonists referred to as mu agonists. This means they bind to the receptor and produce a response. Agonists for different opioid receptors are believed to relieve different types of pain. This would explain why morphine may not work as well for pancreatic pain, but another opioid analgesic does. Other opioids (nalbuphine, butorphanol) are partial agonists because they initiate kappa receptors but partially block mu receptors. Buprenorphine (Suboxone) is a partial agonist combined with naloxone that is only approved for use in the treatment of opioid dependence. Other partial agonist opioids are identified in Table 19:2. Finally, drugs like naloxone and methylnaloxone are
pure antagonists. These drugs do not produce effects but bind to the receptor so that other agonists cannot and, in this way, reverse the mu effects of opioids.
Pharmacological Effects Like the endogenous peptides, opioid analgesics produce effects on a variety of tissues. Opioid receptors are widely distributed outside the CNS, such as in the gastrointestinal and urinary tract. In addition to modifying pain perception, the endogenous peptides modify mood, and regulate cardiovascular, respiratory, and endocrine function. This explains how the opioid analgesics produce their classic side effects of sedation (mu, kappa), euphoria (mu), dysphoria (kappa), constipation (mu), urinary retention (mu), miosis (mu, kappa), and respiratory depression (mu). Chapter 19 • Opioid Analgesics
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Effects on CNS Opioid analgesics may influence CNS function by increasing or decreasing certain CNS activity. For example, opioid analgesics do not cause a loss of consciousness at therapeutic doses. However, these drugs do alter mental behavior. In particular, opioid analgesics produce changes in mood and decrease mental alertness. Some individuals experience a feeling of well-being—a warm glow—known as euphoria. By activating mu receptors in certain areas of the brain, opiates and the endogenous opioid peptides inhibit the release of GABA (the principal inhibitory neurotransmitter in the brain). Removing GABA allows dopaminergic neurons to fire more vigorously. The release of extra dopamine causes the intensely pleasurable experience of euphoria. This pleasant experience may entice the individuals to use the drug continually, thus contributing to the development of drug dependency. This is a highly variable response because other individuals may experience dysphoria, an unpleasant reaction, which enhances anxiety and fear. Dysphoric individuals are less likely to abuse these drugs. In low doses, most opioid analgesics produce nausea and vomiting. Emesis (vomiting) is a direct result of activation of delta or kappa receptors causing CNS stimulation of the chemoreceptor trigger zone, which in turn leads to direct stimulation of the vomiting center Figure 19.3
in the medulla. In some individuals, the frequency of vomiting increases when the patient is standing or moving. As the dose of opioid is increased, the drug exerts a depressant action on the vomiting center by activating mu receptors. Therefore, at large doses, opioid analgesics counteract their own emetic response by inhibiting the vomiting center (Figure 19.3). Vomiting may not be a serious side effect incurred with the treatment of chronic pain. Understanding the mechanisms and substrates involved in vomiting is important because opiates are used as adjuncts to anesthesia and for postoperative pain control where vomiting can be detrimental to the procedure and recovery process. One of the most important CNS effects produced by these analgesics is respiratory depression. All dose levels of opioid analgesics depress respiratory activity. Activation of mu2 receptors directly inhibits the respiratory centers in the medulla and the pons. Respiratory rate and volume are reduced so that carbon dioxide (CO2) is retained in the blood. Mild retention of CO2 may produce headaches because CO2 increases cerebral fluid pressure and intracranial pressure. As respiratory depression increases, so does CO2 retention. However, the suppressed medulla cannot respond to CO2 stimulation, and hypoventilation persists. The depth of respiratory depression increases as the dose of the
Opioid Analgesic Effects on the Vomiting Reflex: Chemoreceptor Trigger Zone (CTZ), Vomiting Center (VC), and Stomach
Vomiting reflex: CTZ to VC to stomach
Emesis (vomiting)
Low (therapeutic) doses of opioids stimulate delta or kappa receptors in the CTZ to initiate emesis
CTZ VC
High doses of opioids activate mu2 receptors that inhibit the VC and counteract any CTZ stimulation so emesis does not occur
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drug increases. Death due to opioid poisoning is usually attributed to respiratory arrest.
Effects on Smooth Muscle Opioids have spasmogenic activity through a direct action on smooth muscle and mu2 receptors in the GI tract. Opioid analgesics increase smooth muscle tone, causing intermittent muscle contractions or spasms. When spasms occur within the intestinal smooth muscle, peristalsis is inhibited. These analgesics inhibit parasympathetic stimulation of the intestines by blocking the release of acetylcholine. Both of these effects can result in constipation, which frequently occurs with the use of opioid analgesics. Three opioid derivatives—loperamide (Immodium), diphenoxylate (Lomotil), and difenoxin (Motofen)—are used in the treatment of persistent diarrhea. Difenoxin (Motofen) is a mu receptor agonist, chemically related to meperidine, that stimulates mu receptors in the myenteric plexus to decrease peristalsis and constrict sphincters. It also has a direct effect on circular smooth muscle of the bowel that prolongs gastrointestinal transit time. Diphenoxylate is metabolized to difenoxin, which produces the effect. These drugs will be discussed further in Chapter 34. Many opioid analgesics, especially morphine, produce spasm of the common bile duct, which causes pressure to increase in the gallbladder. Usually, this effect is accompanied by intense pain. However, in the presence of an opioid, the painful warning may be eliminated, although the pressure continues to increase. For this reason, opioids such as morphine should be used with caution in patients with possible biliary obstruction. Opioid analgesics affect bronchial smooth muscle by two actions. In addition to their spasmogenic action, these analgesics cause the release of histamine, which directly constricts the bronchioles (see Chapter 31). Constriction of the bronchioles narrows the respiratory passages, making breathing more difficult. This response is dangerous in individuals who already have respiratory difficulties, such as chronic bronchitis, obstructive lung disease, and asthma. Asthmatic patients may be unusually sensitive to histamine release, to the point that opioid analgesics may induce an asthmatic attack. Urine formation and urination are both decreased by opioid analgesics, since these drugs stimulate the secretion of antidiuretic hormone (ADH), which allows the kidneys to reabsorb water. This decreases the volume of urine produced. In addition, spasmogenic activity (mu receptors) of the ureters and sphincter muscles inhibits urine from passing out of the bladder. The combination of these effects usually produces oliguria (a smaller than normal amount of urine) rather than anuria (no formation of urine).
Effects on Cardiovascular System Opioid analgesics do not depress cardiac function in therapeutic doses. This lack of effect is important because it allows these drugs to relieve the pain accompanying myocardial infarction without worsening the condition. Although the cardiac muscle is not affected, bradycardia may occur via mu receptors. Hypotension may occur due to histamine release and medullary vasomotor depression. Hypotension is frequently encountered when changing from a sitting position to a standing position (orthostatic hypotension).
Effects on Eyes Most opioid analgesics produce miosis. This effect is caused by stimulation of the mu receptors in the brain. Most opioid analgesics produce pinpoint pupils in toxic doses. However, meperidine produces mydriasis (dilation). Therefore, the pupil size cannot be used to determine what drug was used by unconscious (overdose) patients. LO 19.4
DRUG ADMINISTRATION Opioid analgesics are frequently administered on a repeated schedule (every 4 to 8 hours) to relieve moderate to severe pain. To be effective, these analgesics must be given before intense pain is present. It is important, therefore, that these analgesics be administered on time, as scheduled. Adherence to the prescribed schedule ensures that patients have an adequate blood level of drug to sustain an analgesic effect. If the next dose of drug is significantly delayed, the pain will recur and may be enhanced by psychological factors associated with anticipation of discomfort. The opioids are available for oral and parenteral administration. Parenteral formulations are used more in surgery and postsurgical recovery. Oral preparations are used to treat acute and chronic pain. All of the oral formulations should be swallowed, never chewed. The amount of drug that can be released as a burst from chewing the tablet could achieve a higher blood level than expected with an increase in side effects. Oral preparations are available for extended release (ER) and immediate release (IR). Morphine capsules (Avinza), hydromorphone (Exalgo), and oxymorphone (Opana ER) are modified-release formulations that permit once-a-day dosing for moderate to severe pain in patients requiring 24-hour pain relief. Immediate-release tablets provide the fastest blood levels from oral absorption. Once the effective analgesic blood level is achieved, the patient may be switched to a controlled-release formulation that Chapter 19 • Opioid Analgesics
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releases drug over 8 to 12 hours. In this way the duration of analgesia is increased. Even with sustained-release formulations, patients often experience breakthrough pain that requires immediate attention. Immediate-release formulations and the ultra-rapid-acting fentanyl buccal tablets and lozenges treat breakthrough pain. Recently there has been a significant change in the attitude and methods regarding the treatment of chronic severe pain. Specialists in pain and symptom management use aggressive drug treatment schedules where dosing is often under the control of the patient. In order to ensure the drug is being taken before intense pain has developed, in hospitals, patients may be using patientcontrolled analgesia (PCA). PCA allows the patient to use the lowest effective dose of opioid before the pain intensity becomes unbearable. In effect, the patient Figure 19.4
278
minimizes the opportunity for dependence through lower dose exposure and a customized administration schedule. Drug delivery systems also have improved. Examples of opioid preparations are presented in Figure 19.4. A transdermal patch and transmucosal lozenge are now available forms of fentanyl that are used for the treatment of chronic pain. Transmucosal lozenges are sucked rather than swallowed or chewed. An absorbable film that sticks to the inside of the cheek delivers fentanyl (Onsolis) to the oral mucosa. The formulation is indicated for the management of severe flares of breakthrough pain in patients already taking opioids. Because fentanyl is subject to abuse and misuse, Onsolis was approved for use in accordance with a risk management program and is restricted to eligible prescribers participating in the program.
Opioid Analgesics Available as Tablets, Nasal Spray, and Transdermal Patches
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Opioid analgesics are CNS depressants at any dose. It is therefore important to monitor vital signs when patients, especially the elderly, are receiving these drugs. Indications of decreased blood pressure or respiration may be a clue that patients have been overmedicated and are experiencing cardiovascular or respiratory depression.
Absorption and Metabolism Since these analgesics are weak bases, these drugs are not well absorbed in the acid environment of the stomach. They are absorbed in the intestines, where the pH is more alkaline. Regardless of the route of administration, metabolic inactivation of the opioid eventually occurs in the hepatic drug microsomal metabolizing system. Heroin is a particularly dangerous drug because it is not metabolized to an inactive product. Heroin is rapidly changed into a very active molecule, morphine. Several opioids are metabolized to products that produce analgesia. A clinical benefit is maintained because the circulating active metabolites increase the duration of analgesic activity. Eventually, the kidneys excrete the metabolic products. Anything that causes the urine to become alkaline, such as alkalosis and diuretics (see Chapter 24), increases Figure 19.5 Site of Action of Methylnaltrexone
Opioid
mu-opioid receptor
mu-opioid receptor
Methylnaltrexone
tubular reabsorption of the opioids. This action elevates the concentration of drug in the blood and increases the risk of developing drug toxicity. LO 19.5 5
LO 19.7 7
LO 19.9
A DVERSE E FFECTS, TOLERANCE, AND P HYSICAL D EPENDENCE The most common effects produced by these analgesics include mental confusion, nausea, vomiting, dry mouth, constipation, and urinary retention. Constipation is bothersome, especially in the treatment of cancer patients. An opioid antagonist, methylnaltrexone (Relistor), is used to reverse such GI effects. Methylnaltrexone bromide selectively blocks peripheral mu-opioid receptors without affecting receptors in the CNS. It is approved for treatment of opioid-induced constipation in patients with advanced illnesses or palliative care who receive opioids for pain relief. (See Figure 19.5.) One subcutaneous injection every other day, but no more frequently than every 24 hours, is the recommended dosing frequency. Dosage is individualized to the patient by weight. In sensitive individuals, histamine release produces hypotension and allergic reactions ranging from itching, skin rashes, and wheals to anaphylaxis. Therefore, it is important to determine whether patients are allergic to any opioid before administering one. Several, but not all, opioids have black box warnings in their instructions for use. Fentanyl, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and propoxyphene have special cautionary warnings that emphasize the level of abuse liability is highest among these opioids. Deaths from respiratory depression have occurred. Patients must not consume alcohol or medications containing alcohol while on these products because of the synergy to depress the CNS, especially respiration. Certain preparations, for example, morphine capsules (Kadian) 100 and 200 mg, are not recommended for treatment of non-opioid-dependent patients. The extended-release formulations hydromorphone (Exalgo) and oxymorphone (Opana ER), the transmucosal fentanyl (Onsolis), and the dosage strength Kadian are intended only for the management of opioid-tolerant patients. These drugs are not for the management of acute or postoperative pain.
Tolerance This opioid antagonist stops opioid agonists (analgesics) from interacting with the mu receptor in the intestines.
The effects associated with the chronic use of opioid analgesics are the development of tolerance and physical dependence. Tolerance may result from several changes in the opioid receptors. Desensitization of mu and kappa Chapter 19 • Opioid Analgesics
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receptors may be involved, where the G protein does not couple with the opioid as before. The neurotransmitter glutamate and the NMDA receptor may regulate the amount of opioid receptors so that fewer are available for coupling. Although the opioid is present in increasingly larger amounts, it has fewer competent receptors to produce the responses. Tolerance develops to the euphoria, analgesia, sedation, and respiratory depression produced by the opioid analgesics. Tolerance does not develop equally to all opioid effects. When tolerance develops to sedation, drowsiness, or respiratory depression, this is a beneficial response. If, however, the degree of pain has not changed, but the dose of drug must be increased to achieve relief of pain, this is analgesic tolerance, which is not beneficial to the patient. (If pain increases, as occurs with cancer patients, and the dose of opioid is increased to cover the escalating pain, this is not tolerance.) At sufficiently large doses, even tolerant individuals will die from severe respiratory depression (arrest). The onset of tolerance varies with the analgesic. On the other hand, tolerance seldom develops to the annoying spasmogenic effects such as constipation and urinary retention. Cancer patients usually take larger doses of opioids and may experience intolerable opioid side effects. Opioid rotation is a term used to indicate a change of opioid analgesic that may produce fewer side effects. Therefore, cross-tolerance to opioid effects is relative to the patient’s condition and the specific opioid.
Physical Dependence and Addiction Treatment Physical dependence upon any opioid can develop with chronic use of the analgesic. This means that with sustained use the body reacts (withdrawal syndrome) to sudden removal or rapid dose reduction of the drug. Many people, including medical professionals and patients who have access to opioid drugs (especially meperidine), develop physical dependence. Even infants who are exposed to opioids through the placental blood can be born physically dependent upon these drugs. Controlled gradual tapering of the medication over time (days to a week) enables the person to move off the medication with little withdrawal effect. Physical dependence is not the same as addiction. Addiction is a complex interaction of genetic, psychological, and socioenvironmental factors that describe behaviors in the individual and lack of control over drug use. Pain management with opioids, especially under adequate medical supervision, does not by itself cause addiction. The mechanism by which addiction occurs is not fully understood; however, it is now considered a primary disease rather than a side effect of drug usage. 280
Once addiction is established, the opioid is required to avoid the onset of withdrawal (abstinence syndrome). The abstinence syndrome associated with these analgesics gradually develops over the 72 hours following the last exposure. During the initial period of withdrawal, sweating, yawning, restlessness, insomnia, and tremors occur. As the syndrome reaches its peak, blood pressure and irritability increase, accompanied by vomiting and diarrhea. Excessive sweating, gooseflesh, chills, and skeletal muscle cramps develop toward the end of the withdrawal period. Individuals who are addicted to these analgesics usually survive the withdrawal period. Administration of an opioid at any time during the withdrawal period will suppress the abstinence syndrome. Administration of an opioid antagonist in a patient with addiction will precipitate a withdrawal reaction. Other CNS drugs such as barbiturates, alcohol, or amphetamines cannot suppress opioid withdrawal. Methadone is particularly useful in the treatment of addiction because it satisfies the opioid hunger so that the individual actually becomes acclimated to methadone. Methadone does not produce severe withdrawal symptoms and the symptoms occur gradually during the 6to 7-week maintenance compared to 72 hours for other opioids. Since oral methadone is half as potent as parenteral methadone, it is easier to withdraw patients from methadone gradually without incurring a severe abstinence syndrome. Levomethadyl acetate is another drug that is only used for the management of opiate addiction. The newest drug to treat addiction is buprenorphine. Buprenorphine is a partial agonist/antagonist that is used for the management and treatment of addiction. It has a high affinity (binding) for mu receptors so it pushes other opioids out of the way, blocking their attachment to receptors. As a partial agonist, it exerts a limited opioid effect, enough to reverse the withdrawal effects without producing euphoria. Buprenorphine is available for oral (Subutex) or parenteral (Buprenex) administration, but the preferred choice for maintenance therapy is the combination buprenorphine and naloxone (Suboxone). Treatment begins (induction) when the patient has begun to experience withdrawal symptoms. Buprenorphine alone is given 8 mg on the first day and 16 mg the second day. Thereafter, during maintenance, the patient takes the combination drug available with 0.5 or 2 mg of naloxone. The presence of naloxone precludes development of euphoria in the event of posttreatment exposure to opioids. The breakthrough with buprenorphine/naloxone therapy is that it improves patient acceptance and compliance. It permits induction in the physician’s office with maintenance at home by prescription. Currently, this drug is limited to use
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by specially certified physicians who conduct treatment programs in accordance with the Drug Addiction Treatment Act of 2000.
LO 19.5 5
LO 19.6 6
LO 19.7 7
LO 19.9
Cautions and Contraindications
O PIOID A NTAGONISTS AND R ESPIRATORY D EPRESSION
Opioid analgesics should not be used in patients with bronchial asthma, heavy pulmonary secretions, convulsive disorders, biliary obstruction, or head injuries. In these cases, opioids may worsen the existing condition. Ambulatory and elderly patients should be warned about the drowsiness that may accompany the use of opioid analgesics. Since opioid analgesics will cross the placental barrier and affect fetuses, use of these drugs during pregnancy should be minimized. Short-term exposure of the fetus at term (from use of these drugs at parturition) presents relatively little potential danger to the newborn. Opioid analgesics should never be used when a nonopioid analgesic is indicated to relieve the pain. Whenever opioid analgesics are to be administered intravenously, naloxone should be readily available.
Opioid antagonists are drugs that attach to the opioid receptors and displace the analgesic. Displacement rapidly reverses life-threatening respiratory depression. There are two types of antagonists—pure antagonists and partial antagonists ( Table 19:3). Pure antagonists, such as naloxone and nalmefene, are competitive blocking drugs. Naloxone occupies the mu, delta, and kappa opioid receptors but has no agonist activity (stimulation). Naloxone inhibits the analgesic from attaching to the receptors but does not produce any pharmacological action of its own. Methylnaltrexone bromide (Relistor) is a relatively new drug that selectively blocks peripheral mu-opioid receptors without affecting receptors in the CNS. It is approved for treatment of opioid-induced constipation in patients with advanced illnesses or palliative care who receive opioids for pain relief. One
Table 19:3
Opioid Antagonists Used to Treat Opioid Analgesic Respiratory Depression or Addiction Drug (Trade Name)
Type of antagonist
Adult dose
Treatment of respiratory depression Naloxone (Narcan)
Pure
0.4–2 mg repeated at 3-min intervals IM, SC, IV
Nalmefene (Revex)
Pure
Individualized dose by weight
Buprenorphine (Subutex)
Partial
12–16 mg maintenance dose PO, sublingual
Buprenorphine and naltrexone (Suboxone)
Partial, pure
12–16 mg PO maintenance dose, 0.5 or 2 mg dose sublingual
Naltrexone (ReVia)
Pure
Methadone (40 mg) (Intensol)
—
Only after the patient has been opioid-free for 7–10 days; maintenance dose 50 mg every 24 hr 15–20 mg PO initially; 40 mg for those dependent on high opioid doses
Methadone diskettes (40 mg)
—
2.5–10 mg PO, IM, SC every 3–4 hr
Levomethadyl (Orlaam)
—
Maintenance dose 60–90 mg three times a week
Treatment of addiction
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Note to the Health Care Professional Opioid antagonists cannot be used to reverse the respiratory depression produced by other drugs, such as barbiturates and alcohol. In fact, the partial antagonists may worsen respiratory depression, whereas naloxone has no deleterious effect in these situations. Opioid antagonists should not be administered to individuals who are addicted to opioids because withdrawal symptoms will occur.
subcutaneous injection every other day, but no more frequently than every 24 hours, is the recommended dosing frequency. Dosage is individualized to the patient by weight. Partial antagonists such as butorphanol, nalbuphine, and pentazocine have two actions on the respiratory system. These drugs produce weak morphine-like effects in normal individuals, resulting in respiratory depression. In cases of acute opioid poisoning, however, partial antagonists reverse the respiratory depression. Partial antagonists bind with the receptors and produce little or no stimulation of the receptors which mediate respiratory depression. Today, the drug of choice in the treatment of acute opioid poisonings is naloxone because it does not produce any respiratory depression. Opioid overdose, or acute poisoning, frequently occurs from accidental ingestion (children), attempted suicide, or exposure of a fetus during pregnancy. The symptoms of poisoning include coma, decreased respiration, cyanosis, hypotension, and a fall in body temperature. Once patients are adequately ventilated with a respirator, the poisoning can be treated with specific opioid antagonists such as naloxone. LO 19.3 3
LO 19.4 4
LO 19.9
OPIOID ANTITUSSIVES Codeine, hydrocodone, and dextromethorphan are antitussive, which means they effectively suppress the cough reflex at therapeutic doses. Dextromethorphan and codeine are the most commonly used antitussives. They are considered to be much less potent analgesics than morphine and possess a lower addiction liability. The antitussive effect is produced by direct inhibition of the coughing center in the medulla. These drugs do not 282
cure the underlying cause of the irritation; they merely decrease the intensity and frequency of the cough. Once the cough reflex has been suppressed, patients become less irritable and less anxious and are usually able to sleep comfortably. Among the antitussive drugs, codeine and hydrocodone are natural derivatives of opium, whereas dextromethorphan is a synthetic product. Dextromethorphan or very small amounts of codeine have a recognized therapeutic value associated with a lower addiction potential compared to other opioid analgesics when used in recommended doses for short periods. Codeine and dextromethorphan have come under close scrutiny because of the potential for misuse, especially among people under 18 years of age. Dextromethorphan is an active ingredient in more than 100 OTC products. Nonprescription products containing these drugs have been used to achieve a “cheap high” among some people under 18. Concern has prompted attempts to change current regulations in order to restrict the sale of such products to minors. While a change in the current regulations to restrict dextromethorphan has not yet occurred, proposals are ongoing at the federal and state levels. Meanwhile, some stores have voluntarily moved dextromethorphan products behind the counter to alter access. Codeine alone and hydrocodone (Dicodid ) are Schedule II drugs (recognized medical benefit although associated with high abuse potential with severe dependence liability). Codeine in mixtures or combination, depending on the amount present, may be Schedule III or V. Dextromethorphan is the only opioid that is not a scheduled drug. It is exempt (not included in the list) from the Controlled Substances Act. The adult antitussive dose of codeine is 10 to 20 mg every 4 to 6 hours. For dextromethorphan, a dose of 15 to 30 mg is recommended over the same time interval. For children 6 to 12 years of age, one-half the adult dose is usually recommended. Table 19:4 compares antitussive doses for the opioid antitussive drugs. These drugs are considered effective for the treatment of a nonproductive cough that is unable to mobilize phlegm (mucus). Dextromethorphan is frequently found as the principal drug in over-the-counter cough and cold preparations. The more potent antitussive drugs (hydrocodone) are not a sole ingredient in over-the-counter cough suppressant remedies. Cough suppression may be only one objective in relieving the symptoms of a cold. Additional objectives of therapy include relieving nasal congestion, reducing pain and fever, and promoting bed rest through sedation. It is not surprising, therefore, that agents such as expectorants, antihistaminics, sympathomimetics, and alcohol are present in various combinations in
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Table 19:4
Analgesic Combination Products Trade Name
Schedule
Antitussive dose
Other active ingredients
Fioricet with codeine
III
30 mg codeine
325 mg acetaminophen, 50 mg butalbital
Lortab elixir
III
2.5 mg hydrocodone
167 mg acetaminophen, 7% alcohol
Percocet
II
2.5 mg oxycodone
325 mg acetaminophen
Percocet, Roxicet
II
2 or 5 mg oxycodone
325 mg acetaminophen
Percodan, Roxiprin
II
4.5 mg oxycodone hydrochloride and 0.38 mg oxycodone terephthate
325 mg aspirin
Tylenol with codeine elixir
V
12 mg codeine
120 mg acetaminophen, 7% alcohol
Tylenol with codeine tablets
III
15 mg codeine sulfate
300 mg acetaminophen
Vicodin ES tablets
III
7.5 mg hydrocodone
750 mg acetaminophen
Vicodin tablets
III
5 mg hydrocodone
500 mg acetaminophen
Vicoprofen tablets
III
7.5 mg hydrocodone
200 mg ibuprofen
over-the-counter cold and cough preparations. These other active ingredients (for example, antihistaminics, sympathomimetic amines) may counteract the potential for abuse. Expectorants (ammonium chloride, guaifenesin, and terpin hydrate) are often combined with antitussive drugs to alter the volume and viscosity of mucus retained in the respiratory tract. Expectorants promote the discharge of mucus from the respiratory tract, thus reducing chest irritation and congestion. Sympathomimetic amines (ephedrine, phenylephrine, phenylpropanolamine, and pseudoephedrine) are combined with antitussive drugs to produce nasal decongestion by constricting nasal blood vessels. The antihistamines that are H1-antagonists, such as chlorpheniramine and pyrilamine, exert an anticholinergic action, which may decrease secretion of mucus, whereas alcohol may act as a CNS depressant. It is not unusual to find that liquid preparations contain alcohol, some in excess of 15 percent. (Consider the possible CNS interactions that may occur when these products are used in addition to other prescription medications.) Table 19:5 lists examples of combination over-the-counter preparations that contain an opioid
antitussive as the principal active drug. Examples of OTC products containing dextromethorphan are shown in Figure 19.6. Note the concentration of the antitussive product as well as the types of additional pharmacological agents in each preparation. Although this is not an exhaustive list of available products, notice the various amounts of alcohol present in even pediatric liquid preparations. No wonder some of these products are recommended for bedtime use; they certainly can promote sleep. LO 19.8
D RUG I NTERACTIONS A few specific drug interactions occur with these analgesics. Opioid analgesics potentiate the depression of any CNS depressant drug (sedative-hypnotics, alcohol, and general anesthetics). Meperidine undergoes an unusual, potentially fatal, reaction when used in the presence of monoamine oxidase (MAO) inhibitors. Sweating, hypotension, or hypertension may occur in patients taking meperidine with pargyline, phenelzine, or tranylcypromine concomitantly. Dextromethorphan has been reported to undergo a similar interaction with Chapter 19 • Opioid Analgesics
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Table 19:5
Combination Over-the-Counter Preparations Containing Opioid Antitussive Drugs* Trade Name
Antitussive
Liquid concentration
Other ingredients
Amount of alcohol
Benylin cough
10 mg dextromethorphan
2.0 mg/ml
Ammonium chloride, sodium citrate
5%
Children’s Nyquil
5 mg dextromethorphan**
1.0 mg/ml
Pseudoephedrine, chlorpheniramine
—
Cheracol D
10 mg dextromethorphan
2.0 mg/ml
Guaifenesin
4.8%
Dimacol caplets
10 mg dextromethorphan
—
Guaifenesin, pseudoephedrine
—
Multisymptom Tylenol Cold
15 mg dextromethorphan
1.0 mg/ml
Chlorpheniramine, pseudoephedrine,
—
Naldecon-DX child’s syrup
10 mg dextromethorphan
1.0 mg/ml
Guaifenesin, phenylpropanolamine
5%
Novahistine DH liquid
10 mg codeine***
0.4 mg/ml
Pseudoephedrine, chlorpheniramine, guaifenesin
5%
Novahistine DHX syrup
10 mg dextromethorphan
2.0 mg/ml
Pseudoephedrine
10%
Nyquil nighttime cold medicine
5 mg dextromethorphan**
1.5 mg/ml
Pseudoephedrine, doxylamine, acetaminophen
25%
Robitussin A-C
10 mg codeine**
2.0 mg/ml
Guaifenesin
3.5%
Robitussin-CF liquid
10 mg dextromethorphan**
2.0 mg/ml
Guaifenesin, phenylpropanolamine
4.8%
Tylenol cold medication, non-drowsy
15 mg dextromethorphan
—
Pseudoephedrine, acetaminophen
—
Vicks Formula 44D
10 mg dextromethorphan**
2.0 mg/ml
Pseudoephedrine
10%
Vicks Formula 44M
10 mg dextromethorphan**
1.5 mg/ml
Pseudoephedrine, chlorpheniramine, acetaminophen
—
*Not an all-inclusive list of available products. **Dose of dextromethorphan reduced from earlier formulation. ***Dose of codeine increased from earlier formulation.
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Figure 19.6
Over-the-Counter Preparations Containing Dextromethorphan
phenelzine. As a result, dextromethorphan should not be given to patients who are receiving MAO inhibitors. Rifampin and phenytoin have been associated with reduction in the plasma concentrations of methadone sufficient to induce withdrawal symptoms. Certain opioid analgesics may be administered as parenteral solutions; therefore, it is important to be aware of incompatibilities that may result in drug inactivation.
Codeine, levorphanol, meperidine, and morphine have been reported to be physically incompatible when mixed in solution with aminophylline, barbiturates, chlorothiazide, heparin, methicillin, phenytoin, sodium bicarbonate, or sulfisoxazole. Pentazocine is incompatible with solutions of aminophylline, barbiturates, glycopyrrolate, and sodium bicarbonate. Meperidine should not be mixed with solutions containing morphine.
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Patient Administration and Monitoring Although opioid analgesics are frequently used in a controlled environment such as a hospital or rehabilitation center, there is considerable opportunity for outpatient use of prescription as well as over-the-counter analgesics. This potentiates the possibility for adverse reactions and/or drug interactions to occur. Patient vital signs should be monitored, especially respiration rate, to determine whether dose adjustment is required. Elderly patients require careful instruction for identifying adverse effects and contacting the physician. Specific signs such as confusion, drowsiness, forgetfulness, and impaired coordination or vision may be ignored as part of the aging process when, in fact, the degree of debilitation may be caused by the dose, frequency, or combination of medications. Written instructions for contacting the physician should be provided in large, easy-to-read type, in a format that can be carried with the patient for easy reference.
Patient Instruction Patients must be instructed not to chew, break, or crush medications. Oral formulations must be swallowed intact to avoid bursts of drug absorption. Avinza (morphine) capsules may be opened and sprinkled on applesauce prior to ingestion, but the individual beads should not be crushed or mashed to avoid rapid release of the drug. As a class, these drugs cause drowsiness, sedation, dizziness, and blurred vision in therapeutic doses. Patients should be interviewed to determine whether they perform tasks that require special equipment or machinery (such as operating a sewing machine, drill press, or assembly tools), coordination, or physical dexterity. As coordination and judgment may be impaired during therapy, extra caution must be in place, including identifying a relative, coworker, or on-site medical person who is aware of the medication schedule. If necessary, alternate transportation may be advisable, particularly in older patients. Patients should be instructed to move slowly and cautiously when getting out of bed or walking. Postural hypotension as well as drowsiness may contribute to unsteady conditions, particularly in elderly patients.
Dose Adjustment Advise patients to check with the physician before taking over-the-counter preparations, particularly cough/cold preparations. Alcohol and CNS depressants enhance the opioid depressant effects. Advise patients to take the drugs as prescribed. Patients should be advised not to change dose or dose interval unless instructed by the physician. For full analgesic effect, the drug must be taken before intense pain occurs.
Gastrointestinal Effects If gastrointestinal upset occurs after oral administration, the patient can be advised to take the medication with meals or milk. If nausea, vomiting, or constipation persists, the physician should be notified for further evaluation. Constipation, a common problem with older patients, may be potentiated with the opioid analgesics, including overthe-counter preparations. The patient should be evaluated to assess bowel function so that appropriate stool softeners or laxatives may be recommended.
Special Formulations Patients must be instructed on the use of nasal sprays or transdermal patches. Practice in preparation and application using these systems is essential to obtaining good compliance, especially in older patients. For transdermal patch application, the area should be clear of hair. Shaving is not the method of choice because it could irritate the skin and promote absorption of greater amounts of drug. Creams, lotions, and soaps that could irritate the skin or prevent patch adhesion should not be used. Fever or high temperatures of climate can cause the patch to release more drug, resulting in toxicity. Patients should be instructed to clearly identify those times when they may be in hotter climates than usual so that dose adjustment can be considered.
Notify the Physician Shortness of breath or difficulty breathing should be reported to the physician immediately. Hypersensitivity to these drugs is a contraindication for their use. Patients with depressed respiratory function such as chronic obstructive pulmonary disorder (COPD), emphysema, or severe asthma will exhibit respiratory distress from opioid-induced respiratory depression. Any elevation in body temperature, such as fever, that is not associated with flu or cold should be considered as a potential side effect and should be reported to the physician.
Use in Pregnancy Drugs in this class have been designated Food and Drug Administration (FDA) Pregnancy Category C or NR, not rated. Adequate studies in humans have not been conducted so that safety in pregnancy has not been established. However, these drugs may be used when the potential benefit to the pregnant patient outweighs the risks.
Oral preparations should be swallowed, not chewed, except for fentanyl lozenge and buccal film, which are to be dissolved in the mouth.
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Chapter Review Understanding Terminology Answer the following questions. 1. What is an opioid? (LO 19.2) 2. Describe an antitussive effect. (LO 19.3) 3. Define opioid antagonist. (LO 19.2, 19.7) Match the definition or description in the left column with the appropriate term in the right column. ___ 4. The opposite of euphoria. (LO 19.3)
a. ADH
___ 5. Mucus. (LO 19.3, 19.9)
b. analgesic
___ 6. Production of only a small amount of urine. (LO 19.3, 19.5, 19.9)
c. anuria
___ 7. Vomiting. (LO 19.3, 19.5)
d. dysphoria
___ 8. Production of no urine. (LO 19.3, 19.5, 19.9)
e. emesis
___ 9. A substance that inhibits one’s reaction to pain. (LO 19.1, 19.9)
f. oliguria
___ 10. Antidiuretic hormone. (LO 19.3, 19.5)
g. phlegm
Acquiring Knowledge Answer the following questions. 1. What types of pain are relieved by opioid analgesics? (LO 19.1, 19.2, 19.3) 2. What are the therapeutic uses of opioid analgesics? (LO 19.3, 19.7) 3. What is the proposed mechanism of action of opioid analgesics? (LO 19.1, 19.3) 4. What effects do the opioid analgesics have on the CNS? (LO 19.3, 19.5) 5. How might these effects be involved in other drug interactions? What drugs might potentiate CNS respiratory depression? (LO 19.8) 6. What is the spasmogenic action of the opioid analgesics? (LO 19.3, 19.5, 19.9) 7. Why does urine retention occur with the use of opioid analgesics? (LO 19.3, 19.5) 8. Are all opioid analgesics administered orally? Why or why not? (LO 19.4) 9. What adverse effects are associated with opioid analgesics? (LO 19.5, 19.6)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. One of your jobs as a pharmacy assistant is to alert the pharmacist about patients with potential contraindications or drug interactions. What’s wrong with each of the following prescriptions for the patients in question? a. Patient A has been prescribed codeine for severe headaches. Pharmacy records indicate that the patient also takes Metaprel, a bronchodilator prescribed for bronchial asthma. (LO 19.2, 19.3, 19.8) b. Patient B has been prescribed morphine for severe postoperative pain. You note in reviewing his chart that he also takes the drug Moduretic, a diuretic, for hypertension. (LO 19.2, 19.3, 19.8) c. Patient C has been prescribed Demerol for a muscle injury. She’s already taking Nardil for depression. (LO 19.2, 19.3, 19.8)
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Chapter Review Continued 2. For each of the following adult patients, how much opioid is needed to produce the desired effect? (LO 19.2, 19.4) a. Patient A has been prescribed codeine for dental pain. b. Patient B has been prescribed a cough preparation containing codeine. c. Patient C has been prescribed Dilaudid for pain associated with cancer. d. Patient D has bronchitis and has been prescribed Dilaudid for his painful cough. Use the appropriate reference book(s) if needed to answer the following questions. 3. Plain pentazocine was once available in a tablet form. Naloxone was later added to the tablet. Does this interfere with the pharmacological action of pentazocine when taken orally? Why was this added? (LO 19.2, 19.4, 19.7) 4. For several months Jack has been getting Vicodin (hydrocodone 5 mg/acetaminophen 500 mg) from his regular pharmacy. In the last 30 days he has received #280 Vicodin from several different doctors. Would you suspect possible addiction? Would you expect the pharmacy to contact the doctor(s)? Why? (LO 19.2, 19.5) 5. It is not uncommon for drug abusers to alter prescriptions for opioids. Common alterations to watch for include changing the quantities (i.e., 10 to 40, 30 to 80, or adding a 1 in front of the number—20 to 120) and adding refills where none were indicated. Prescribers can help deter this practice by spelling out the quantities and refills or by writing no refill or non rep if no refills are desired. Look at the following prescriptions and see if you notice anything that seems out of place. Then explain what, if anything, is out of place and what you think the pharmacy might do. (LO 19.2, 19.4) a. dental—Vicodin #42—1 po q6h prn dental pain—refill 4 times. b. bone break—Tylenol /codeine 30mg #30—1–2 po q3–4h prn leg pain—refill 4 times. c. cancer patient—morphine Intensol 20mg/ml #120ml—0.25 to 1 ml po q1–2h prn breakthru pain—no refill d. emergency room—Demerol 50mg tablets #110—1 po q4–6h prn migraine pain—0 refills
Multiple Choice Use your critical-thinking skills to answer the following questions. 1. Which of the following is a correct statement? (LO 19.3, 19.4, 19.5, 19.7, 19.9) A. opioid analgesics produce little or no respiration depression with long-term use of analgesic doses B. opioid antagonists include endorphins C. all drugs in the opioid analgesic group are controlled substances, Schedule III D. in low doses, opioids produce nausea and vomiting 2. Oxycodone in therapeutic doses can stimulate mu receptors to cause (LO 19.3, 19.5, 19.7, 19.9) A. hyperventilation and deep breathing B. bronchospasms C. spasmogenic activity in the ureters and sphincter muscle D. relaxation of the skeletal muscles controlling posture (spasmolytic) 3. Opioid analgesics are used in which of the following settings? (LO 19.1, 19.2, 19.3, 19.4) A. induction of Monitored Anesthesia Care and treatment of chronic severe pain B. routine treatment of migraine C. unmonitored treatment of chronic severe pain D. analgesia for patients with paralytic ileus 4. Which of the following is not a pure opioid agonist analgesic? (LO 19.2, 19.3, 19.6, 19.7) A. nalbuphine (Narcan) B. butorphanol (Stadol) C. fentanyl transmucosal (Actiq) D. sufentanil (Sufenta)
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5. Which of the following is a correct statement? (LO 19.1, 19.2, 19.9) A. endorphin is an abbreviation from the terms meaning inside the organ B. endogenous opioid receptors include mu, alpha-2 adrenergic, and delta receptors C. agonism means the drug occupies the receptor and causes a response D. opioid agonism means the drug occupies the receptor and stops endorphins from binding to them 6. Which of the following drugs has a recognized medical therapy and does not interact with opioid receptors? (LO 19.2, 19.3) A. heroin B. codeine C. methadone D. acetaminophen 7. All opioid analgesics are associated with which of the following? (LO 19.2, 19.4, 19.5) A. reversal of respiratory depression from barbiturates B. use only for the relief of acute pain C. cough suppression alone or in combination with other analgesics over-the-counter D. tolerance develops to the analgesic response 8. Fentanyl is an opioid analgesic that (LO 19.1, 19.2, 19.4, 19.9) A. can be used for relief of cancer pain B. has many formulations (lozenge, film) because it is used routinely in dental surgery C. induces neuropathic pain D. primarily works on peripheral nerve endings rather than higher centers
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Sharp pain is transmitted through which type of nerve fibers? (LO 19.1) A. unmyelinated B. myelinated C. A-delta D. C fibers 2. Which opioids are used as antitussives? (LO 19.3) A. sufentanil B. fentanyl C. codeine D. dextromethorphan 3. Opioid drugs are derived from which of the following? (LO 19.2) A. poppy B. opium C. chemical synthesis D. alkaloids 4. Select the adverse effects of opioid analgesics. (LO 19.5) A. constipation B. polyuria C. convulsions D. bradycardia 5. During tolerance to opioid analgesics, the following is happening. (LO 19.9) A. fewer receptors are available to produce a response B. increased pain by the patient requires greater doses of medication C. the body reacts to removal of the opioid analgesic D. histamine release causes hypotension Chapter 19 • Chapter Review
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Chapter Review Continued Sequencing Place the following in order from the most addiction potential to the least addiction potential. (LO 19.3, 19.5, 19.9) _________________
_________________
_________________
_________________
Most
Least
meperidine heroin methadone pentazocine
Classification Place the following under the appropriate analgesic potency. (LO 19.3) sufentanil
levorphanol
pentazocine
heroin
meperidine
oxycodone
hydrocodone
alfentanil
codeine
oxymorphone
hydromorphone
Less than morphine
propoxyphene
Same as morphine
Greater than morphine
Documentation Using the prescription below, answer the following questions. (LO 19.4)
Falls Clinic Practice RX 12345 Main Avenue Anytown, USA 12345 931-555-1000 NAME:
Marge Nester
DATE:
ADDRESS: RX
Morphine 40mg
Sig:
inject subcutaneously
Dr. Warren Fisk Substitution Permitted DEA #:
290
M.D.
M.D. Dispense as written REFILL:
NR
1
2
3
4
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a. b. c. d.
What is the adult dose for morphine injection? Is the dose prescribed within the adult dosing guidelines? What is the duration of action of this medication? How often would this medication likely be administered?
Labeling Fill in the missing labels. (LO 19.3, 19.4, 19.9)
For interactive animations, videos, and assessment, visit:
www.mcgrawhillconnect.com Chapter 19 • Chapter Review
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Chapter 20
Nonopioid Analgesics, Nonsteroidal Antiinflammatories, and Antigout Drugs
DRUG CLASS AT A GLANCE
KEY TERMS
OTC
analgesia: inhibition of the perception of pain.
YES Aspirin, ibuprofen, naproxen, acetaminophen
PRESCRIPTION YES SCHEDULED DRUGS
YES Restricted combinations with butalbital CIII, codeine CIII
FDA P REGNANCY CATEGORY
B, C
anaphylaxis: condition in which the body develops a severe allergic response; this is a medical emergency. anemia: condition in which the number of red blood cells or the amount of hemoglobin inside the red blood cells is less than normal. antiinflammatory: minimizing or stopping the response to tissue injury by reducing the pain, localized swelling, and chemical substances released at the site of injury. antipyresis: reducing an elevated body temperature. arthralgia: joint pain. arthritis: inflammation of the joints.
INDICATIONS Fever; mild to moderate pain, e.g., arthritis, dysmenorrhea, headache; cardioprotection
COX: cyclooxygenase, a family of enzymes that produce prostaglandins. dysmenorrhea: difficult or painful menstruation. erythema: abnormal redness of the skin, caused by capillary congestion. inflammation: condition in which tissues have been damaged, characterized by swelling, pain, heat, and sometimes redness. intoxication: state in which a substance has accumulated to potentially harmful levels in the body.
ischemia: reduction in blood supply and oxygen to localized area of the body or tissue. lavage: washing with fluids or flushing of a cavity such as the stomach. leukopenia: condition in which the total number of white blood cells circulating in the blood is less than normal. megaloblastic anemia: condition in which there is a large, immature form of the red blood cell, which does not function as efficiently as the mature form. myalgia: pain associated with muscle injury. petechia: small area of the skin or mucous membranes that is discolored because of localized hemorrhages. phagocyte: circulating cell (such as a leukocyte) that ingests waste products or bacteria in order to remove them from the body.
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prophylaxis: treatment or drug given to prevent a condition or disease. prostaglandin: substance naturally found in certain tissues of the body; can stimulate uterine and intestinal muscle contractions and may cause pain by stimulating nerve endings. rheumatic fever: condition in which pain and inflammation of the joints or muscles are accompanied by elevated body temperature usually a complication of untreated Strep throat. salicylism: condition in which toxic doses of salicylates are ingested, resulting in nausea, tinnitus, and delirium. selective COX-2 inhibitors: drugs that only interact with one of the enzymes in the cyclooxygenase family.
Learning Outcomes
After studying this chapter, you should be able to
20.4 explain why nonopioid analgesics are particularly effective against inflammation.
20.1 explain the inflammatory process and identify sites where drugs interrupt inflammation.
20.5 describe the primary side effects associated with long-term aspirin and antiinflammatory drug use.
20.2 identify situations in which it is appropriate to select a nonopioid drug for pain relief. 20.3 describe the advantage of selecting acetaminophen over aspirin.
20.6 explain why probenecid, febuxostat, and colchicine are specifically useful in the treatment of gout.
Introduction
Nonopioid analgesics, also known as mild analgesics, relieve mild to moderate pain without altering consciousness or mental function. In particular, these drugs relieve the low-intensity pain associated with inflammation, including that from arthritis and gout, and associated with dull aches, including headaches, arthralgia (joint pain), and myalgia (muscle pain). In addition to reducing mild pain (analgesia), the nonopioid analgesics reduce fever (antipyresis) and reduce inflammation (are antiinflammatory). These three pharmacological effects (analgesia, antipyresis, and antiinflammatory), known as the “three As,” are characteristics of this class.
LO 20.1
INFLAMMATION AND ANTIINFLAMMATORY DRUG ACTION The inflammatory process is a normal response to injury. When tissues are damaged, substances (histamine, bradykinin, prostaglandins, and serotonin) are released that produce vasodilation and increased permeability of the capillary walls (see Figure 20.1). Pain receptors are stimulated, and proteins and fluid leak out of the injured cells. As blood flow to the damaged area increases,
phagocytes (leukocytes) migrate to the area to destroy harmful substances introduced by the injury. These effects result in the development of the cardinal signs of inflammation: redness, swelling (edema), warmth, pain, and loss of function. Inflammation is usually considered the first step in the process of healing. However, in some instances, the inflammatory process becomes exaggerated or prolonged, which results in further tissue damage. In these situations, inflammation itself becomes a disease process and requires treatment with antiinflammatory drugs,
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Inflammatory Tissue Injury
Figure 20.1
Splinter
Tissue damage can result from (a) break in the skin (splinter), (b) acute muscle injury, or (c) chronic degenerative joint disease
From damaged tissue 1
Inflammatory chemicals
Bacteria From mast cells From blood
5 Phagocytosis (b)
4 Chemotaxis Increased permeability
Mast cells
3 Neutrophils
2 Margination
Diapedesis
Blood capillary or venule
(c)
(a) Inflammatory response (1) Chemical messengers are released by damaged tissue, basophils, and mast cells. These inflammatory chemicals stimulate white blood cell activity such as (2) adhesion to the capillary wall (margination), (3) diapedesis (crawling through the capillary wall), (4) chemotaxis (movement toward the source of the inflammatory chemicals), and (5) phagocytosis (engulfing bacteria or other pathogens).
which interrupt the inflammatory response. These drugs inhibit prostaglandin synthesis so that nocioceptors (free nerve endings) do not have to respond to painful, irritating stimuli, and tissue edema is resolved. Prostaglandins are mediators of the inflammatory response (Figure 20.2). Prostaglandins are formed in the cell membranes of most organs. Prostaglandins do not travel great distances (like hormones) to their receptors. The target tissue where prostaglandin receptors are located is usually in the same general location as prostaglandin production. Enzymatic conversion of membrane phospholipids forms the parent of all prostaglandins, arachidonic acid, a fatty acid. This fatty acid undergoes further conversion through the enzyme cyclooxygenase to form prostaglandins G2 and H2. These intermediates are converted to several prostaglandins (Figure 20.3) that 294
are amazingly similar but different enough to interact with 10 unique receptors. Prostaglandins in conjuction with histamine and bradykinin are capable of stimulating peripheral pain receptors, constricting (PGE2) or dilating (PGF2α) blood vessels, elevating body temperature (fever PGE1), and contracting (PGF2α) or relaxing (PGE2) smooth muscles of the bladder, intestines, bronchioles, and uterus. Prostaglandin PGE2 is involved in the production of erythema (abnormal redness), edema, and pain that accompany the inflammatory process; PGF2α is associated with uterine contraction and vasodilation. Figure 20.2 indicates two major enzyme locations (phospholipase A2 and cyclooxygenase) where prostaglandin synthesis can be interrupted to minimize the local inflammatory response. The site of inhibition
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Figure 20.2
Prostaglandin Production from Phospholipids of the Cell Membrane and Sites of Antiinflammatory Drug Action
Phospholipids of plasma membrane Phospholipase A2
Blocked by antiinflammatory steroids cortisol, hydrocortisone, and prednisone
O C
OH Blocked by NSAIDs such as aspirin and ibuprofen
Arachidonic acid Mediators for asthma and allergy
Lipoxygenase
Thromboxane A2 stimulates vasoconstriction and platelet adhesion. Irreversibly blocked by aspirin
Cyclooxygenase COX-1,COX-2
Leuk Leukotrienes
OH
Prostacyclin Thromboxanes Prostaglandins
OH
O C
OH
O
OH
Leukotriene B4
C OH
Platelet plug
OH
OH
Collagen fibers
PGF2␣, PGE2
Stimulate pain receptors. Produce erythema, edema, fever Contract or relax smooth muscle
(a) Production of arachidonic acid through phospholipase A 2 . Site of steroid inhibition of prostaglandin synthesis. (b) Production of prostaglandins from arachidonic acid through cyclooxygenase. Site of nonsteroidal antiinflammatory drug (NSAID) inhibition of prostaglandins.
differentiates one antiinflammatory drug class from another. Steroidal antiinflammatory substances (cortisol, hydrocortisone, prednisone) inhibit the formation of arachidonic acid. NSAIDs selectively inhibit the cyclooxygenase enzymes. Cyclooxygenase (COX) is a family of enzymes required to make prostaglandins from arachidonic acid. These enzymes are also called “prostaglandin synthetase,” but COX is the newer terminology. The type of prostaglandin produced is dependent upon the specific
cell (e.g., platelets versus uterine muscle) and the type of cyclooxygenase present. Two subtypes of cyclooxygenase have been identified: COX-1 and COX-2. COX-1 is believed to always be available in all cells, especially in the platelets, kidneys, and gastrointestinal tract, so that homeostasis in these cells is maintained. COX-2, on the other hand, appears to be manufactured in activated macrophages in response to injury or damage to local tissues. Aspirin affects the cyclooxygenase pathway, reducing inflammatory prostaglandins, and it inhibits
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the thromboxane pathway, making it useful as an anticoagulant (see Figure 20.2). NSAIDs ease the pain and headache of dysmenorrhea. Ibuprofen has been reported to suppress uterine PGF2 even more than PGE2, making it useful in the treatment of dysmenorrhea. Ocular NSAIDs are used after corneal surgery to block disruption of aqueous humor blood barrier and reduce intraocular pressure. Nonsteroidal antiinflammatory drugs ease the symptoms associated with inflammation because they inhibit prostaglandin synthesis in many different tissues in the inflammation pathway.
Clinical Indications Nonsteroidal antiinflammatory drugs are approved for the relief of mild to moderate pain where opioids are not indicated or warranted. This includes pain arising from local inflammatory responses including headache, dental extraction, soft tissue injury, sunburn, musculoskeletal, and joint overexertion and strain. Because of the direct action on regional prostaglandin production, NSAIDs also are indicated for the chronic treatment of dysmenorrhea, and for controlling the signs and symptoms of osteo- and rheumatoid arthritis. Antiinflammatory drugs vary in their ability to reduce all types of inflammation, which may be indicative of a selective interference at enzymatic sites within the prostaglandin synthesis pathway. Sulindac (Clinoril ), tolmetin (Tolectin), meclofenamic acid (Ponstel ), meclofenamate (Meclomen), and piroxicam (Feldene) are antiinflammatory drugs used in the treatment of a variety of inflammatory conditions, such as tendinitis, bursitis, rheumatoid arthritis, osteoarthritis, and dysmenorrhea (difficult or painful menstruation). Nonsteroidal antiinflammatory drugs may be used for short periods (up to 7 days) for the relief of acute inflammation. It is not uncommon, however, for these drugs to be taken for longer periods. In osteoarthritis, a degenerative joint disease, joint movement may be compromised so that movement is painful and difficult (stiff). Pain may occur in the absence of overt signs of inflammation. Although analgesics such as aspirin are indicated, it is still advisable to have patients avoid stressing the involved joints (take weight off the joints and rest). Rheumatoid arthritis, also a degenerative joint disease, is associated with inflammation of the joint cartilage. Often, inflamed joints are noticeably warm to the touch, are difficult to move (especially in the morning), and become immobile or deformed through the course of the disease. For the treatment of osteoarthritis, spondylitis (inflammation of the vertebrae), and gout, aspirin can be the drug of choice. 296
The treatment of dysmenorrhea has markedly improved with the advent of the NSAIDs. Also known as menstrual cramps, dysmenorrhea is characterized by uterine contractions, local vasoconstriction (ischemia), and pain. In addition, headache, nausea, vomiting, and diarrhea may occur. Evidence suggests that women who suffer the discomfort of dysmenorrhea may have higher levels of uterine prostaglandins, especially PGF2a and PGE2, than nondysmenorrheic women. Nonsteroidal antiinflammatory drugs are effective in relieving the symptoms of dysmenorrhea and are much better than low doses of aspirin. LO 20.1 1
LO 20.3 3
LO 20.4 4
LO 20.5
NONOPIOID ANALGESICS: SALICYLATES (ASPIRIN) Nonopioid analgesics differ from opioid analgesics in four ways. First, these analgesics are not chemically or structurally related to morphine (nor are they related to each other by a common structure). Second, they are not effective against severe, sharp (visceral) pain. Third, they produce analgesia through both a central (central nervous system [CNS]) and a peripheral (site of injury) mechanism of action. Fourth, they do not produce tolerance or physical dependency with chronic use. These drugs are also known as nonsteroidal antiinflammatory drugs (NSAIDs) because they are not structurally related to cortisone (adrenal steroid) and produce their antiinflammatory action through a different mechanism. Cortisone is a potent antiinflammatory hormone used in specific inflammatory diseases, often when other nonsteroidal agents have not been effective. (Cortisone is discussed in Chapter 36.) There are three groups of nonopioid analgesics: salicylates and aspirin (the original NSAIDs), acetaminophen, and the synthetic NSAIDs such as ibuprophen, indomethacin, and ketoprofen. Several nonopioid analgesics are listed in Table 20:1. Nonsteroidal antiinflammatory drugs (NSAIDs) are the largest class of nonopioid analgesics. There are three groups within this class, distinguished by their prominent pharmacologic action: salicylates, traditional NSAIDs, and COX-2 selective inhibitors. This large class of drugs will be presented in two parts: salicylates and traditional NSAIDs. The salicylates, represented by aspirin and salicylic acid, are the oldest and most frequently used nonopioid analgesic drugs that are analgesic, antipyretic, and antiinflammatory. This group will be presented first because of its historical prominence in pain management and because it is the most widely used drug in the United States.
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Table 20:1
Recommended Adult Oral Doses of NSAID (Nonopioid) Analgesics Analgesic and antipyretic (including dysmenorrhea)
Antiinflammatory (osteoarthritis, rheumatoid arthritis, ankylosing spondylitis)
325–650 mg every 4 hr 1300 mg every 8 hr, maximum daily dose 4 g
Not specifically antiinflammatory; used as short-term adjunct to other therapy
Aspirin (Ascriptin, Bayer, Bufferin, Ecotrin)*
325–1000 mg every 4–6 hr
In divided doses; maximum daily dose 4 g
Aspirin (extra strength)
500 mg every 3 hr
1000 mg every 6 hr
Salicylic acid (Amigesic, Arthra-G, Salflex)**
1500 mg BID
3 g/day TID
Drug (Trade Name)
N-acetyl-p-aminophenol Acetaminophen (Tylenol )*
Salicylates
Synthetic nonsteroidal antiinflammatory drugs *** Diclofenac (Cataflam, Voltaren, Zipsor)**
50 mg TID
100–200 mg/day
Diflunisal (Dolobid )**
500–1000 mg every 8–12 hr
500 mg BID; 500–1000 mg/day
Etodolac**
200–400 mg every 6–8 hr
600–1200 mg/day
Fenoprofen (Nalfon)**
200 mg every 4–6 hr
300–600 mg TID, QID
Flurbiprofen (Ansaid )**
Not indicated for this
200–300 mg up to QID
Ibuprofen (Advil, Motrin, Nuprin)* (available by prescription in 300 mg or more)**
200–400 mg every 4–6 hr
600 mg QID; 300–800 mg QID
Indomethacin (Indocin)**
Not indicated for this
25–70 mg TID
Ketoprofen**
25–50 mg every 6–8 hr
300 mg/day for immediate release; 200 mg/day for extended release
Ketorolac tromethamine (only used after IV/IM therapy)**
Short-term management of moderate to severe acute (surgical) pain, 10 mg every 6 hr; not to exceed 5 days. Black box warning for use
—
Meclofenamate (Meclomen)**
50–100 mg every 4–6 hr
200–400 mg/day
Meclofenamic acid, meclofenamate (Ponstel )**
250 mg every 6 hr; dysmenorrhea also. NSAID class warning
Meloxicam (Mobic)
Not indicated for this
7.5–15 mg/day (long half-life 20 hrs)
Nabumetone**
Not indicated for this
1000 mg QD, BID (long half-life 26 hrs)
Naproxen (Aleve, Midol, extended relief )*
200 mg every 6–8 hr
550 mg BID or 275 mg every 6–8 hrs; maximum daily dose 1100 mg
Naproxen (Anaprox, Naprelan, Naprosyn)**
200 mg every 6–8 hr dysmenorrhea also
250–500 mg BID (Continued)
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Table 20:1 Continued Analgesic and antipyretic (including dysmenorrhea)
Antiinflammatory (osteoarthritis, rheumatoid arthritis, ankylosing spondylitis)
Oxaprozin (Daypro)**
Not indicated for this
1200–1800 mg QD (long half-life 58 hrs)
Piroxicam (Feldene)**
Not indicated for this
20 mg/day (long half-life 57 hrs)
Sulindac (Clinoril)**
Not indicated for this
200 mg BID; 400 mg/day
Tolmetin**
Not indicated for this
400 mg TID up to 1800 mg/day
Not indicated for this
200 mg/day
Drug (Trade Name)
Selective COX-2 Inhibitors Celecoxib (Celebrex)**
*Available over the counter. **Available by prescription. ***These drugs are antipyretic and analgesic but are primarily used for their antiinflammatory actions. All NSAIDs have a class warning for use in patients with myocardial infarction, CABG (coronary artery bypass graft), and gastrointestinal bleed potential.
The traditional NSAIDs, represented by ibuprophen and naproxen, and the sole COX-2 inhibitor, celecoxib, will follow. Traditional NSAIDs are primarily used for their antiinflammatory action. Finally, the analgesic and antipyretic drug acetaminophen will be presented, followed by the drugs used for the clinical management of gout. Salicylates were discovered centuries ago as a natural product of the willow tree bark. Native Americans drank teas and beverages made from willow bark to relieve headaches and toothaches. The salicylates used today include sodium salicylate, aspirin (acetylsalicylic acid), salicylamide, and methyl salicylate. Methyl salicylate (oil of wintergreen, Ben-Gay, Deep-Heat) is the only salicylate that is a poison when taken orally. Methyl salicylate is used topically (creams) to produce cutaneous irritation, which increases blood flow and warmth at the site of application. The other salicylates (aspirin) are weak acids that are rapidly absorbed from the stomach and small intestine following oral administration.
Analgesia and Antipyresis The centers of the brain that regulate pain and temperature are located in the hypothalamus. Nonopioid analgesics, including salicylates, are thought to produce analgesia and antipyresis by selectively affecting the hypothalamic centers, reducing an elevated body temperature but not affecting normal body temperature. The mechanism of the central action involves blockade of prostaglandin stimulation of the central nervous system (CNS). In addition to the central action, these drugs increase peripheral blood flow (vasodilation) and 298
sweating, permitting a greater loss of excess heat from the body. Analgesia is produced by affecting both the hypothalamus and the site of injury. In response to tissue injury, joint damage, or edema, active substances such as bradykinin, prostaglandins, and histamine are released. Prostaglandins and bradykinin, in particular, stimulate peripheral nerve endings, which carry pain impulses to the CNS. Nonopioid analgesics inhibit the synthesis of prostaglandins and prevent bradykinin from stimulating pain receptors. Since prostaglandins also affect hypothalamic centers, nonopioid analgesics inhibit the recognition of pain impulses centrally and peripherally. Aspirin is the most potent inhibitor of prostaglandin synthetase in the salicylate group. Headache is caused by a variety of stimuli; it can result from vascular, allergic, or local pain triggers. (See Figure 20.3.) Aspirin is particularly useful in the treatment of headache because inhibition of COX inhibits the formation of prostaglandins thus reducing vascular permeability and release of other neurotransmitters involved in pain generation.
Antiinflammatory Action Salicylates are excellent antiinflammatory drugs. They are effective in reducing inflammation because they inhibit a primary pathway in prostaglandin synthesis. These drugs are antiinflammatory, inhibiting both COX-1 and COX-2. The development of inflammation and the action of the salicylates upon this response was presented in the section on Inflammation and Antiinflammatory Drug Action.
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Figure 20.3
Headache Caused by Prostaglandin-Mediated Pain and Vascular Permeability (Edema) Membrane phospholipids
Corticosteroids Phospholipase A2 NSAID
Arachidonic acid
Cyclooxygenase COX
PGG2
Hydroperoxidase
PGH2
PGF synthetase
PGE synthetase
PGI synthetase
PGD synthetase
TXA synthetase
PGI2
PGD2
TXA2
Angiogenesis Miosis Vascular permeability
PGE2
Allergic reactions
PGE9 Intoreductase
PGF2α
Increases outflow within ocular tissues
Gastrointestinal Effects Salicylates directly irritate the stomach mucosal lining. Many people are sensitive to this action and experience nausea after taking aspirin. In addition, salicylates inhibit prostaglandin synthesis. In the stomach, prostaglandins are an integral part of the normal cytoprotective mechanisms. Prostaglandins mediate secretion of mucus and bicarbonate, which protect the lining of the stomach from erosion by gastric acid. When COX-1 is blocked, the protective environment within the stomach is altered, leading to gastric distress and ulcers. In some individuals, vomiting occurs as a result of gastrointestinal (GI) irritation and CNS stimulation. Salicylates
stimulate the medullary center known as the chemoreceptor trigger zone. This zone directly excites the vomiting center so that emesis may occur.
Anticoagulant and Cardiovascular Benefit Aspirin and salicylamide irreversibly inhibit the aggregation of platelets necessary for blood clot formation. Aspirin permanently hinders the access of arachidonic acid to the active site on the COX-1 enzyme (see Figure 20.2). As a result, even low doses of aspirin increase bleeding time. In large doses, salicylates may depress the formation of other coagulation factors (prothrombin),
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Note to the Health Care Professional Use of nonaspirin NSAIDs like ibuprofen or celecoxib with chronic low-dose aspirin therapy reduces (antagonizes) the beneficial cardiovascular effect of aspirin. NSAIDs attach to a site on the COX-1 enzyme and competitively inhibit aspirin from producing its antiplatelet action on COX-1. This reduced prophylactic action is observed as “aspirin resistance.” NSAIDs used more than 60 days per year with daily aspirin also contribute to aspirin resistance.
thus increasing bleeding time. Petechial (localized) hemorrhages that occur in aspirin-sensitive patients are partially due to the anticoagulant actions. With doses of aspirin greater than 6 g per day, prolongation of prothrombin time is clinically significant. This may be significant and requires close monitoring in patients with clotting disorders. Of therapeutic significance is the fact that aspirin reduces the risk of death and reinfarction following myocardial infarction (MI). Low-dose aspirin daily lowers the risk of heart attack and prevents heart disease and a second heart attack in women over 65 years old and men at any age. Women benefit from aspirin therapy because the risk of first stroke also is reduced. This has not been shown to occur in men. The results of many studies conclude that this cardiovascular benefit warrants its prophylactic daily use. This prophylactic action is directly related to irreversible inhibition of platelet aggregation and has no effect once a clot has formed. Decreased platelet aggregation (prophylaxis against clots and stroke) is mediated by COX-1. Aspirin is unique because it covalently (tight bonding) modifies COX so that new COX enzymes must be synthesized to replace the bound inactive complex. (This is why relatively small amounts of aspirin affect platelets for more than a day. As aspirin is being absorbed, platelets moving through the intestines have their COX permanently blocked. New COX forms only with the synthesis of new platelets.) In patients with atrial fibrillation who cannot take warfarin (oral anticoagulant), adult-strength aspirin daily may be used to provide anticoagulant protection. These anticoagulant effects increase the potential for hemorrhage in certain patients—that is, those sensitive to salicylates or receiving other anticoagulants or those predisposed to intestinal ulcers. In specific 300
cardiovascular-compromised patients where ulcers are present, chronic administration of aspirin may be beneficial to prevent the formation of thromboemboli. While it does appear contradictory, the use of aspirin in such a circumstance would reduce the greater risk of emboli forming or reaching the brain, lung, or heart.
Metabolism and Excretion Following absorption, salicylates readily bind to plasma proteins (80 to 90 percent). In this way, salicylates are distributed to various tissues, especially the CNS, joint fluids, and kidneys. Eventually, these drugs are metabolized in the liver and excreted into urine. Plasma levels of salicylates are affected by the pH of the urine. Acidic urine permits these weak acids to be reabsorbed by the renal tubules and reenter the blood. In contrast, alkaline urine increases the excretion of salicylates. Urine pH can change in response to acid-base imbalance, drug therapy, or renal impairment.
Adverse and Toxic Effects In low doses, salicylates relieve pain, aches, and fever. However, to relieve the pain of arthritis, gout, and rheumatic fever, salicylates must be used in large doses for long periods of time. Large-dose therapy is more frequently associated with toxic reactions (chronic intoxication). However, acute salicylate intoxication also may occur from accidental ingestion of large amounts of drug. Accidental overdose is more likely to occur with children than with adults. Chronic salicylate intoxication produces nausea, vomiting, or salicylism. Salicylism is a series of symptoms that include nausea, ringing in the ears (tinnitus), headache, delirium, and hyperventilation. These effects are due to CNS stimulation and subside when the dose is reduced or the drug is terminated. In addition, hyperglycemia may occur due to increased sympathetic tone. A cultural contribution to the development of salicylate intoxication may come from the patient’s diet. Many foods are known to contain salicylates naturally, such as curry powder, paprika, licorice, prunes, raisins, tea, and gherkins. It has been estimated that the American diet may contain 6 to 200 mg of salicylates per day. Hypersensitivity to aspirin may produce skin rashes, laryngeal edema, and asthma. Such reactions may be lifethreatening, so that hypersensitive patients must avoid all products containing aspirin. Salicylates are readily available as over-the-counter (OTC) drugs, either alone or in combination with other products. Examples of drug mixtures that contain nonopioid analgesics are presented in Table 20:2. Such products are present in almost every home, and many times they are found by adventurous
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Table 20:2
Drug Mixtures That Contain Nonopioid Analgesics*** Trade Name
Amount of nonopioid analgesic
Alka-Seltzer, Ascriptin, Bufferin
325–500 mg aspirin
1700–2085 mg sodium bicarbonate 1000 mg citric acid
—
Aspirin
650 mg aspirin
—
—
Bromo-Seltzer
325 mg acetaminophen
2781 mg sodium bicarbonate 2224 mg citric acid
—
Bufferin Extra Strength
500 mg aspirin
—
—
Darvocet-N 50*
325 mg acetaminophen
50 mg propoxyphene
IV
Darvocet-N 100*
650 mg acetaminophen
100 mg propoxyphene
IV
Darvon Compound-65*
389 mg aspirin
32.4 mg caffeine, 65 mg propoxyphene
IV
Equagesic*
325 mg aspirin
Meprobamate 200 mg
IV
Fiorinal*
325 mg aspirin
40 mg caffeine, 50 mg butalbital (barbiturate)
III
Midol IB, Advil, Menadol, Pamprin-IB
200 mg ibuprofen
—
—
Maximum Strength Midol PMS capsules and gelcaps
500 mg acetaminophen
25 mg Pamabrom**, 15 mg pyrilamine
—
Pamprin Maximum Cramp Relief
500 mg acetaminophen
Pamabrom**, pyrilamine
—
Panacet 5/500
500 mg acetaminophen
5 mg hydrocodone
III
Panadol Children’s
80 mg acetaminophen
—
Percodan*
325 mg aspirin
4.5 mg oxycodone HCI, 0.20 mg oxycodone terephthalate
II
Percocet*
325 mg acetaminophen 500 mg acetaminophen 650 mg acetaminophen
2.5, 5, 7.5, or 10 mg oxycodone 7.5 mg oxycodone 10 mg oxycodone
II II II
Tylenol with Codeine* No. 2, No. 3, and No. 4
300 mg acetaminophen
15, 30, or 60 mg codeine
III
Tylox capsules*
500 mg acetaminophen
5 mg oxycodone
II
Vanquish**
204 mg acetaminophen
227 mg aspirin, 33 mg caffeine, magnesium hydroxide and, aluminum hydroxide
ZORprin*
800 mg aspirin
—
Other active drugs
Schedule
—
*Available by prescription only. **Over-the-counter diuretic. ***Not an all-inclusive list of available products.
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children. Attracted by the colored tablets or candy flavor, children often ingest a toxic amount of analgesic. There is a cautionary safety warning associated with the use of salicylates specifically directed at its use in children. Children and teenagers should not use salicylates for chickenpox or flu symptoms before a doctor is consulted because of the possibility for Reye’s syndrome to occur.
Acute Toxicity The dangerous and often fatal reactions of acute salicylate poisoning involve respiratory depression and acidosis. Toxic doses of salicylates depress the medullary respiratory centers so that individuals cannot remove carbon dioxide (CO2) rapidly, leading to respiratory acidosis. Other acids accumulate in the blood because renal function is impaired. Salicylates and tissue waste products (lactic acid) cannot be cleared from the body. Individuals enter respiratory and metabolic acidosis, and the blood and urine pH values fall. Profuse sweating causes dehydration, and sodium, potassium, and protein excretion in the urine may increase. Cardiovascular function is depressed, resulting in vasodilation and hypotension. The acute lethal dose is estimated to be 10 to 30 g for adults and 4 g for children. Treatment of salicylate poisoning includes administration of sodium bicarbonate to correct the acidosis and to increase salicylate excretion (increase urine pH). In addition, fluid and electrolytes are infused to correct the hypotension and acid-base balance. Treatment of salicylate poisoning is not always successful. Coma and death may result from dehydration, extensive CNS depression, and renal failure.
Clinical Indications Salicylates, especially aspirin, are used in mild to moderate pain. This is pain that is not associated with the need for opioids. Inflammation contributing to headache and to muscle and joint pain, including osteoarthritis and rheumatoid arthritis, is reduced and often eliminated by these drugs. Aspirin is the cornerstone in treatment and prevention of cardiovascular disease. Low-dose aspirin (50 to 100 mg daily) reduces the risk of developing myocardial infarction, transient ischemic attacks (TIAs), and stroke. Clinical management of acute myocardial infarction and stroke requires doses greater than 160 mg daily. Because of the special action on platelet aggregation, aspirin is indicated for use in patients with unstable angina pectoris, TIAs, and stroke, and to reduce the risk of death in men and women with MI. For years patients have been told to take low-dose aspirin to reduce the risk of stroke and myocardial infarction. More recently the data 302
from long-term studies in patients taking daily aspirin have been reevaluated. The consensus is that long-term aspirin therapy reduces the development of adenomatous polyps and colorectal cancer. As any long-term therapy may be associated with the onset of side effects, patients who have more than average risk for developing colorectal cancer may be the primary group to benefit from this aspirin treatment strategy. Salicylates that are related to or metabolized to 5-ASA (acetylsalicylic acid) are widely used in the management of ulcerative colitis. Balsalazide (Colozal ), mesalamine (Asacol, Pentasa, Rowasa), olsalazine (Dipentum), and sulfadiazine (Azulfidine, Azulfidine EN tabs) are administered orally to act within the colon to influence prostaglandin production and activity there. The mechanism of action of these drugs is not specifically known.
Dose and Formulation Availability Because of its long-standing use, aspirin has become widely acceptable as safe for use in adults and children. To accommodate the wide spectrum of use, aspirin and salicylates are available in a variety of oral formulations ranging from tablets, capsules, and gum to solutions and liquids more easily swallowed by children. While aspirin is available over-the-counter (OTC) alone or in combination with a wide variety of other active ingredients, a prescription is required for products containing greater than 650 mg of aspirin per tablet (see Table 20:1 for examples). Pediatric dosing is based on age and weight, with two 81-mg pediatric tablets (age 2 to 3 years) equal to one-half of a 325-mg adult tablet, every 4 hours. At age 6 to 8 years, the dose is four 81-mg tablets or one adult tablet (325 mg). By age 12 to 14 years, dosing is at the recommended adult level of two (325-mg) tablets (see Table 20:3).
Note to the Health Care Professional Aspirin use in children, including teenagers, who have active viral infections or chickenpox has been associated with the development of Reye’s syndrome. Although rare, this condition can be life-threatening. The symptoms range from vomiting and belligerence to delirium and coma. Death has occurred in some children. Although the mechanism has not been fully characterized, various professional and government organizations advise against the use of aspirin in young adults or children with active flu or chickenpox.
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Table 20:3
Pediatric Oral Dosing Guidelines for Aspirin and Acetaminophen — Dose Every 4–6 Hours
LO 20.1 1
LO 20.2 2
LO 20.3 3
LO 20.4 4
Age
Acetaminophen
Aspirin
0–3 months
40 mg
—
4–11 months
80 mg
—
1–2 years
120 mg
—
2–3 years
160 mg
162 mg
4–5 years
240 mg
243 mg
6–8 years
320 mg
324 mg
9–10 years
400 mg
405 mg
11 years
480 mg
486 mg
12–14 years
640 mg
648 mg
14 years
650 mg
650 mg
LO 20.5
ACETAMINOPHEN Acetaminophen is often considered an aspirin substitute. However, this assumption is not entirely correct. Acetaminophen (Datril, Panadol, Tylenol ) produces adequate analgesia for the relief of a minor headache and antipyresis but has no proven antiinflammatory activity. It reduces elevated body temperature by a direct action on the heat regulation centers in the hypothalamus, postulated to occur through the COX-3 receptors. Acetaminophen has been a puzzle because it suppresses pain and fever but has relatively little effect on inflammation or the secretion of stomach acid. More recent evidence suggests that it may act on another COX, tentatively called COX-3, that is mainly found in the brain. Acetaminophen is effective against the pain of headache because it inhibits prostaglandin synthetase within the CNS but is not a drug of choice in the treatment of pain associated with muscle aches and inflammation, especially arthritis. Acetaminophen does not significantly inhibit the synthesis of prostaglandins in peripheral systems, which accounts for the lack of antiinflammatory activity. For the relief of headache or the symptomatic relief of cold and flu, aspirin-sensitive patients may substitute
acetaminophen because acetaminophen does not produce GI irritation or ulceration in therapeutic doses. Acetaminophen does not affect platelet aggregation or prothrombin response.
Clinical Indications Acetaminophen is approved to reduce fever, headache, minor musculoskeletal pain, and discomfort associated with the common cold and flu. It is particularly indicated for use in patients allergic to aspirin, those receiving anticoagulant therapy for coagulation disorders, or patients who have upper GI disease and for whom aspirin therapy is not an option. It is recommended for use in patients who experience GI upset from aspirin or nonsteroidal antiinflammatory drugs (NSAIDs); however, it is not interchangeable with these products for chronic therapy of inflammatory conditions such as osteoarthritis. No benefit has been associated with the use of this drug in stroke or infarction.
Dose and Formulation Availability Acetaminophen is available in OTC products in doses ranging from 80 mg (pediatric) to 650 mg per tablet,
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capsule, or caplet. Dosing guidelines are available for infants 0 to 3 months (40 mg), 4 to 11 months (80 mg), and 1 to 2 years of age (120 mg). The pediatric and adult doses of 325 mg every 4 hours coincide at the recommendation for 6 to 8 years of age. It is recommended that the adult daily dose not exceed 4000 mg, while the pediatric exposure should not exceed 5 doses in 24 hours ( Table 20:3). Because of its acceptability for use in children, acetaminophen is available in a variety of formulations ranging from suppository to solution, elixir, suspension, and syrup. At all doses and formulations, acetaminophen is available without prescription, OTC. For best shelf-life, suppositories should be refrigerated between use.
Adverse Effects Although remarkably safe when taken in recommended doses, acetaminophen is not a harmless drug. Toxicity may develop from chronic use of large doses of acetaminophen (more than 4 g/day in adults and 75 mg/kg/ day in children with febrile illnesses) as well as acute overdose from a single episode of ingestion of a large dose (such as an accidental overdose of 200 mg/kg in children and 6 g in adults). There are no specific early warning signs of acetaminophen toxicity. The course of poisoning may follow several stages. During the first 24 hours after ingestion, the patient may be asymptomatic; then nausea and vomiting may occur. This period often resembles “flu-like” feelings to the patient and is, therefore, ignored as evidence of toxicity. During the next 24 hours, hepatic serum enzymes may rise (AST/ SGOT, ALT/SGPT, bilirubin, thrombin). Elevations in AST/SGOT may exceed 20,000. Within 36 hours of ingestion of a toxic dose, hepatic damage may result. Deaths have occurred following acetaminophen overdose. Overdose of acetaminophen also produces acidosis and respiratory complications similar to those described for salicylate poisoning. Treatment for acetaminophen poisoning includes gastric aspiration and lavage (washing with fluids) as well as maintenance of fluid balance through conventional measures. Activated charcoal has been used for decades as a general sequestrant of oral poisons; it will decrease the absorption of acetaminophen if administered within hours of the ingested overdose. There is, however, an approved antidote for toxic acetaminophen overdose. N-acetylcysteine (NAC, Acetadote) is the antidote for toxic acetaminophen overdose. It is usually given by mouth; however, the odor is particularly foul and has to be mixed with palatable liquids or juices to get patient compliance and to minimize its irritation on the stomach lining. Otherwise, it 304
is given intravenously. The oral dose is repeated over 72 hours to ensure maximal detoxification of the active metabolite, whereas the intravenous route may complete the effect in half the time. N-acetylcysteine stimulates the metabolic system (glutathione) that binds (conjugates) the toxic metabolite and removes it from the body. NAC also facilitates the metabolism of the remaining acetaminophen to a nontoxic product. N-acetylcysteine successfully prevents liver damage when administered intravenously or orally within 10 hours of acetaminophen poisoning. The intravenous route may be preferred over the oral route of administration because detoxification can be accomplished in 24 hours with fewer dosings. The intravenous route has been associated with anaphylactoid reactions (allergic reaction) such as flushing, rash, urticaria, hypotension, and bronchospasm. These effects are seen more often in patients with a history of asthma or obstructive airway disease after the initial loading dose of NAC and can be medically managed with intravenous administration of an antihistamine. N-acetylcysteine has been available for years as a mucolytic in cystic fibrosis patients; however, a specific intravenous formulation has been prepared for use in toxic overdose of acetaminophen.
Special Considerations Acetaminophen is used in more combination products than any other drug in doses from 160 to 500 mg per dose. It has been estimated that one-third of the people in the United States take acetaminophen in some form at least once a month. While taken within the recommended doses for appropriate indications, it is still relatively safe and effective. There is an expectation for the over-the-counter products that relatively safe means more is better without risk. When patients take acetaminophen (Tylenol ) for pain and then use multiple OTC products for relief of cold and flu symptoms, especially in addition to alcohol, there is an increased risk of developing liver toxicity. The excessive use of acetaminophen causes metabolites of the drug to bind to tissue groups in the kidney and liver, causing hepatotoxicity. Liver transplantation is often the only treatment to prevent death. People who consume more than three alcoholic beverages per day have potential hepatic sensitivity that becomes compromised with increased exposure to acetaminophen. The FDA has continued to express a concern that adults and children are at risk for developing an acetaminophen toxicity through overdose because flavored medications attract children to these medications and adults frequently take “more than the recommended dose striving to eliminate moderate to severe pain.” Acetaminophen has been reported to be associated with liver failure
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in children. Among adults, there is a risk of increased exposure because the large daily doses used by some patients for arthritis (4 to 6 g/day) are compounded by frequent use of the “nonaspirin” headache or cold and flu remedies. Also, the risk of exposure is increased with use of opioid analgesic combination drugs like Vicodin, Tylox, or Percocet. Finally, in 2009 the FDA took action to require stronger language in the label for acetaminophen, warning about the risk of developing liver injury with acetaminophen use. This will be required of any acetaminophen-containing product whether an over-the-counter or prescription product, or a single entity or combination product. There is also a recommendation to remove acetaminophen from all combination products, especially those containing strong opioid analgesics, or to place a cautionary boxed warning in the labeling for these products. There is a recommendation to reduce the maximum allowed daily dose of acetaminophen from 4 to 2.6 g per day. Reducing the recommended maximum individual dose from 1000 to 650 mg will not change habits of patient use where more than two or three tablets are taken, exposing the patient to the same total drug exposure. Organ-specific safety information and dose recommendations are directed to the attention of the consumer/patient, not just medical personnel. This also will be the case for identifying the known drug interaction of acetaminophen with warfarin. Acetaminophen has been reported, in doses of 2 g/day for a week, to increase the anticoagulant effect of warfarin. The mechanism— inhibition of the liver enzyme metabolism of warfarin, resulting in increased circulating anticoagulant—also has been reported to occur with lower-dose exposure (e.g., several 325-mg tablets). For patients taking warfarin, acetaminophen should be taken at the lowest effective dose for short-term therapy only. Coagulation status should be monitored via INR one to two times per week when starting or stopping acetaminophen therapy of more than 2 g per week.
is, any COX will do. To develop better NSAIDs that relieve pain and inflammation but do not cause gastric problems, drugs were designed that selectively interacted with COX-2. The newest generation of NSAIDs, celecoxib (Celebrex), is a selective COX-2 inhibitor that alleviates pain and reduces inflammation by inhibiting only COX-2. Pain relief is not superior to that of the older NSAIDs; it is equal to that of the other NSAIDs. While the incidence of ulcers and gastric bleeding is less, patients have reported gastrointestinal effects similar to those of aspirin.
Drug Administration, Absorption, and Metabolism NSAIDs are available primarily for oral administration. Only ibuprofen (Advil) and naproxen (Aleve, Midol Extended Relief) are currently available OTC (see Figure 20.4). These nonprescription preparations are extremely popular with the general public for the treatment of osteoarthritis (mild to moderate pain, including rheumatoid complications). For the same spectrum of indications, these NSAIDs require a prescription for tablet strengths greater than 300 mg (ibuprofen) and 250 mg (naproxen). Other NSAIDs are available only by prescription. Only three NSAIDs are available for parenteral administration: ibuprofen (Neoprofen), indomethacin (Indocin IV), and ketorolac. Only ketorolac (IM, IV, ophthalmic drops or intranasal spray) is used for the treatment of acute moderate to severe pain “at the opioid level” around surgery (see Figure 20.5). Parenteral ibuprofen and indomethacin are used for a nonanalgesic action: to induce closure of the atrial opening in premature infants with patent ductus arteriosis. The NSAIDs are well absorbed from the stomach following oral administration. Although food may delay drug absorption, it is not uncommon for these drugs to Figure 20.4 Nonprescription (OTC) Products Containing Aspirin, Acetaminophen, Ibuprofen, and Naproxen
LO 20.1 1
LO 20.3 3
LO 20.4 4
LO 20.5
OTHER NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS) Although many of the drugs listed in Table 20:1 produce the same actions as the salicylates, some drugs are only employed for their antiinflammatory effects. All NSAIDs have the ability to interact with cyclooxygenases. Older NSAIDs like aspirin, ketoprofen, and indomethacin are considered nonselective—that Chapter 20 • Nonopioid Analgesics, Nonsteroidal Antiinflammatories, and Antigout Drugs
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Figure 20.5 NSAID ketorolac Preparations: Injection Vial, Eye Drops and Intranasal Spray
be administered with meals, especially in patients who are susceptible to drug-induced gastric irritation. Following oral administration, most of these drugs exert their analgesic action within 30 minutes, with a 4- to 6-hour duration of action. The NSAIDs are highly (more than 90 percent) bound to plasma proteins. For this reason, these drugs undergo many drug interactions due to displacement of other drugs from protein-binding sites. Eventually, these drugs are metabolized by the drug microsomal metabolizing system in the liver prior to renal excretion. Acidification of the urine may result in renal reabsorption of these acidic drugs.
Adverse Effects All antiinflammatory drugs may produce nausea, GI distress, and ulceration. The mechanism of ulceration is 306
Note to the Health Care Professional Patients taking NSAIDs who develop signs of skin rash, visual disturbances, or breathing difficulty should consult their physician immediately.
not exactly known. However, these drugs are thought to inhibit the synthesis of substances (mucopolysaccharides) that protect the stomach from hydrochloric acid erosion. Although ibuprofen has been reported to produce less gastric distress than do other antiinflammatory drugs, any of these drugs may produce ulceration with chronic use. The most serious complication of ulceration is massive hemorrhage, leading to shock and death (see drug warning label for ibuprofen, Figure 20.6). Through CNS stimulation, antiinflammatory drugs may produce vertigo, vomiting, mental confusion, and headaches. Hypersensitivity reactions may include mild rashes, fever, hepatic damage, and respiratory distress in asthmatic individuals. Anaphylaxis has occurred in aspirin-sensitive patients. Aspirin intolerance may occur in patients with a history of nasal polyps, asthma, or rhinitis. In such patients, angioedema and severe rhinitis result from exposure to aspirin-containing products. Megaloblastic anemia, signaled by large, immature red blood cells, has occurred with these drugs because the intestinal absorption of folic acid has been impaired, whereas iron deficiency anemia may occur as a result of blood loss through hemorrhage. Bone marrow suppression leading to blood disorders also has been reported to occur in patients who received NSAIDs. Adverse effects are more likely to occur in patients receiving large doses in the chronic treatment of arthritis, especially rheumatoid arthritis. Overdose of the antiinflammatory drugs produces toxicity similar to that described for salicylates. Treatment is primarily supportive because there is no specific antidote for these agents. The NSAIDs, which include aspirin in large doses (2 to 5 g), will reduce the inflammatory response of various types of arthritis. At these doses, especially in elderly patients, signs of overdose may be present. Primary signs to watch for include ringing in the ears (tinnitus), gastric upset, and GI bleeding (black, tarry stools). To minimize GI side effects, medication may be given with meals, milk, or antacids. Alcohol should be avoided, since it may enhance the adverse gastric action of these drugs.
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Figure 20.6
Warning Label for Nonprescription (OTC) Ibuprofen
The label indicates the potential for stomach bleeding when taken concurrently with other NSAIDS, anticoagulants, and social alcohol intake more than three times a week. The risk of bleeding increases with patients over 60 years of age or who have stomach ulcers.
Age and underlying condition of the patient do influence the onset of adverse effects. The larger dose in combination with patient age over 65 years appears to predispose to the onset of unwanted effects. The best strategy in elderly patients, therefore, requires using the lowest effective dose. Specific newer potent NSAIDs such as ketorolac tromethamine have a special warning that recommends dosage adjustment for patients over 65 years old and/or less than 110 pounds of body weight. Because ketorolac tromethamine is cleared from the body slowly, this may be exaggerated in older patients and patients with renal impairment, as evidenced by elevated serum creatinine levels. In 2009, the American Geriatric Society took a bold step in their guidelines for the use of pain medications in elderly patients. Guidelines were originally issued several years ago promoting the use of NSAIDs to improve pain management and quality of life in older patients. Because patients over 75 years of age often have multiple chronic conditions associated with pain and are usually more susceptible to the adverse effects of NSAIDs, especially the cardiovascular and gastrointestinal effects, the newest guidelines specifically recommend against the use of NSAIDs in elderly patients. It is recommended that patients with moderate-to-severe pain or diminished quality of life due to pain should be considered for opioid treatment rather than NSAIDs. The selective COX-2 inhibitors exhibit potentially more serious cardiac or renal adverse effects than do other NSAIDs because they focus only on one group of enzymes. Two large clinical studies in 8000 patients each suggest that more patients experience an increase in blood pressure (aggravated hypertension), bradycardia,
irregular heartbeat, or chest pains than patients taking other NSAIDs. Evaluation of these clinical data resulted in the removal of two COX-2 inhibitors, rofecoxib (Vioxx) and valdecoxib (Bextra). At present, the only available COX-2 inhibitor is celecoxib (Celebrex). Selective COX-2 inhibitors do not have the antithrombotic (clot prevention) protective action of aspirin and other COX-1 inhibitors because platelets are predominately a COX-1 pathway. NSAIDS and COX-2 inhibitor drugs promote sodium and water retention. This can result in peripheral edema and increase stress on the cardiovascular system in patients with heart failure and hypertension. In the elderly, it can lead to the development of heart and renal failure. Celecoxib should not be taken by patients who have a history of sensitivity to sulfonamides. All selective COX-2 inhibitors have been associated with exacerbating allergic reactions.
Special Considerations Because the therapeutic benefits of NSAIDs are extremely important, the risks are under continual scrutiny by the FDA and medical professionals for appropriate indication and duration of use. When NSAIDs are used in patients receiving certain antihypertensive drugs, blood pressure should be monitored throughout the duration of therapy. NSAIDs reduce the antihypertensive effects of ACE inhibitors (captopril, losartan) on diastolic blood pressure. There is a special cautionary boxed warning for the entire NSAID class of drugs. A boxed warning appears in all nonaspirin NSAID labeling that says that
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all (nonaspirin) NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease (CAD, CVD) or risk factors for cardiovascular disease (history of TIA) may be at greater risk. Nonaspirin NSAIDs are contraindicated for the treatment of perioperative pain (up to 10 to 14 days postoperative) from coronary artery bypass graft (CABG) surgery. NSAIDs cause an increased risk of serious gastrointestinal adverse reactions, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. The FDA has just required NSAID manufacturers to display visibly prominent labels accompanying these
drugs that identify the risks of stomach bleeding. The term “NSAID” must be highlighted on the front label of every product. Every OTC product containing an NSAID will have to include a bolded warning advising consumers about the potential risks for “severe stomach bleeding,” especially in people who • Are aged 60 years or older. • Have had stomach ulcers or bleeding problems. • Take a blood thinning or steroid drug. • Take other drugs containing prescription or nonprescription NSAIDs. • Have three or more alcoholic drinks a day while using the product. • Take more of the product than directed.
Uric Acid Formation and Allopurinol Mechanism of Action
Figure 20.7
Purines O NH2 C
N C C
N C H
C
CH
N H
N
NH2
O
C
NH
C C
Adenine (A)
HN
CH
C
HN
NH
N
C
N
C C
Guanine (G)
O
H N
HN
C Xanthine oxidase
N H
C O
C N H
C C
O
H N
HN
C Xanthine oxidase
N H
Xanthine
Hypoxanthine
C
HN C
N H
C C
O
H C
HN
N N H
Allopurinol
Xanthine oxidase
C O
C N H
C C
O
N H
C C
H N
Excreted in urine C O
N H
Uric acid
(A) Uric acid formation O
C
C
Crystal formation in tissues (joints, kidneys) of goutprone individuals
Februxostat is a more potent inhibitor of xanthine oxidase than allopurinol
H C N N H
Alloxanthine is a noncompetitive inhibitor of xanthine oxidase so no uric acid is formed
Alloxanthine
(B) Allopurinol and februxostat inhibition of uric acid formation (A) Breakdown of purines (adenine and guanine) from DNA and RNA to hypoxanthine. Then xanthine oxidase converts hypoxanthine to xanthine and finally to uric acid. (B) Allopurinol is a noncompetitive inhibitor of xanthine oxidase so uric acid formation is blocked.
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This effort is directed at patients to alert them to the recommended limited dose and duration of treatment in accordance with package instructions. The new labeling requirements were warranted because many consumers are not aware of the risks associated with overdosing of NSAIDs. More importantly, many OTC products contain individual NSAIDs not recognized as an NSAID by the consumer.
LO 20.1 1
LO 20.6
DRUGS USEFUL IN TREATING GOUT Gout is a special inflammatory disease. It is associated with the deposition of uric acid in joint fluid (big toe, knees, and elbows) and soft tissue. Uric acid is formed every day from the metabolism of nucleic acids by the liver (see Figure 20.7 ). If the liver produces 80 percent of daily uric acid, the remaining uric acid load comes from certain foods, such as alcohol, beer, wine, cheeses, beans, anchovies, sardines, liver, kidneys, and cream, that contain a high purine content, which increases the uric acid level of blood (hyperuricemia). Humans cannot use uric acid, so it is normally secreted into the urine by the renal tubules. People who suffer from gout may overproduce uric acid or may not excrete it efficiently. If the uric acid level in the blood exceeds uric acid excretion, resulting in more than 7 mg uric acid/dl blood, a condition of hyperuricemia occurs. Causes of hyperuricemia can be either primary (increased uric acid levels due to purine metabolism and diet) or secondary (high uric acid levels due to another disease or condition). Secondary hyperuricemia occurs in patients with renal disease, where uric acid cannot be excreted and, therefore, accumulates in the blood. It occurs in certain diabetic acidosis conditions that promote changes in cellular (pH) environment and the
Figure 20.8
formation of uric acid crystals. Most importantly, hyperuricemia results from certain cancers, leukemia, and lymphoma where there is a high rate of cell turnover and metabolism contributing to changes in pH that predispose to uric acid crystal formation and deposition in the tissues. Chemotherapy in which there is significant cell death and release of metabolic waste also provides an environment for uric acid crystal deposition. For some unknown reason, uric acid crystals spontaneously accumulate in the joint fluid of gout-prone individuals. Phagocytes (nucleophils, white blood cells) enter the area and attack the uric acid crystals, and this activity leads to a decrease in pH (acid) of the joint fluid, causing more uric acid to accumulate in the joint. This vicious cycle of inflammation produces the edema, redness, and severe pain characteristic of acute gout. In chronic gout, uric acid slowly deposits in soft tissue, causing bulging, deformed joints known as tophi. (Tophaceous deposits may take years to develop; see Figure 20.8.) Uric acid also may accumulate in the kidneys, producing urate stones, which may appear in the urine as sand or gravel. Drugs that are useful in the treatment of gout either relieve the acute inflammatory response or reduce the uric acid levels (uricosuric) in chronic gout. It is worth noting that some patients who suffer intense recurrent bouts of pain with this condition do not have elevated circulating uric acid levels. These agents are listed in Table 20:4.
Treatment of Acute Gout Colchicine’s therapeutic value in the management of gout goes back centuries. It is extremely useful during the first 48 hours of an acute attack. Colchicine, a drug that comes from the crocus plant, specifically alters the ability of the phagocytes to attack uric acid crystals. As a result, the pH of the joint fluid does not fall. Therefore, the cycle of uric acid deposition is interrupted, and the gouty attack eventually subsides.
Deposits of Uric Acid in Patients with Chronic Gout
Tophaceous deposit on the (a) toe, (b) ear, and (c) hand of a patient with end-stage chronic renal disease.
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Table 20:4
Drugs Effective in the Treatment of Gout Drug (Trade Name)
Adult oral dose
Antigout (Acute)
Colchicine
0.5–1.2 mg every 1–2 hr* or 0.5–1.8 mg/day**
Antiinflammatory analgesics
Aspirin***
3–5 g/day
Choline salicylate (Arthropan)***
870 mg every 3–4 hr
Indomethacin (Indocin)
50 mg TID
Naproxen (Naprosyn)
750 mg followed by 250 mg every 8 hr
Sodium thiosalicylate (Rexolate)
100 mg every 3–4 hr
Sulindac (Clinoril )
200 mg BID
Hypouricemic
Allopurinol (Zyloprim)
200–400 mg/day (mild); 400–600 mg/day (severe); 600–800 mg/day (uric acid nephropathy; neoplasias)
Uricosuric
Aspirin
Doses greater than 4 g
Febuxostat (Uloric)
40 or 80 mg once daily
Probenecid
250–500 mg BID
Mixtures
Colchicine (0.5 mg) and probenecid (500 mg)
One tablet daily for 1 week followed by one tablet BID
*Until pain is relieved. **Prophylactic dose. ***OTC; prescription required for all others.
The drug is readily absorbed orally and has good plasma levels within 2 hours. It is excreted into the feces and urine. Colchicine is not an analgesic; it is not a general antiinflammatory drug for the relief of other forms of muscle and joint pain. It is antiinflammatory in the specific condition of acute gout. In 2009, a new colchicine product, Colcrys, was approved to treat acute gout flares as well as for prophylaxis. There is a genetic autoinflammatory condition, Familial Mediterranean Fever (FMF), in which patients periodically experience high fever and abdominal pain. Over the years, colchicine has been given to reduce the acute attack. A significant percentage of FMF 310
patients have received relief with colchicine although the mechanism of action is not understood. Colchicine also prevents the recurrence of aphthous ulcers in these patients. Unfortunately, colchicine frequently produces nausea, vomiting, and diarrhea. Abdominal cramps and blood in the urine (hematuria) also may occur.
Prophylactic Treatment of Gout Prophylactic therapy involves the long-term use of drugs to prevent the occurrence of gouty attacks and tophi. Two major classes of drugs are used in long-term prophylaxis—hypouricemic agents and uricosuric agents.
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Allopurinol and febuxostat (Uloric) are hypouricemic drugs. Allopurinol is also known as an antimetabolite because it resembles the structure of hypoxanthine. Allopurinol inhibits the enzyme xanthine oxidase, which is necessary to turn hypoxanthine into uric acid (see Figure 20.7 ). Therefore, no uric acid is formed, and hypoxanthine is excreted into the urine. Eventually, the uric acid in the blood decreases, preventing the future development of tophi and urate stones in the kidneys. Allopurinol also can be used to reduce the hyperuricemia associated with certain malignancies and other drug therapy (thiazide diuretics). The most common side effects associated with the use of allopurinol are fever, rash, and leukopenia (low white blood cell count). Febuxostat is the first selective xanthine oxidase inhibitor that is not a purine analog. It is used for the chronic management of hyperuricemia in patients with gout. More potent than allopurinol, it inhibits the production of uric acid. This once-daily oral medication is effective at 40 and 80 mg per day. Food and antacids do not affect the absorption of febuxostat. Febuxostat is metabolized by the liver and excreted by the kidney, but dose adjustment is not necessary when used in patients with concomitant conditions of reduced organ function. Colchicine or NSAIDs may be used with febuxostat when a gout flare occurs while establishing the treatment regimen. The flare is a result of uric acid being mobilized from tissue storage sites. Addition of colchicine minimizes or prevents the inflammatory flare. Usually flares can be managed without interrupting the febuxostat regimen. Immunosuppressants mercaptopurine and azothiaprine and the bronchodilator theophylline are drugs metabolized by xanthine oxidase. These drugs should not be given concurrently with febuxostat therapy. Concurrent drug administration would cause an increase in the blood levels of these drugs, potentially leading to adverse effects and toxicity. There have been a few nonserious adverse effects associated with febuxostat, including dizziness, rash, nausea, and temporary elevation in liver enzymes. Monitoring of liver function tests is recommended at two and four months after initiation of therapy and periodically thereafter. The drug is not recommended for use in patients with secondary hyperuricemia. While not contraindicated in patients with myocardial infarction and stroke, it is recommended that patients be monitored while on febuxostat. A higher incidence of cardiovascular thromboembolic events was observed in patients treated with febuxostat compared with allopurinol during clinical trials; however, a causal relationship has not been established. Probenecid is a uricosuric drug used in the chronic management of gout. Uricosuric drugs enhance the
renal excretion of uric acid without altering the formation of uric acid, leading to a rapid clearance of uric acid from the blood. Probenecid inhibits the renal tubule mechanism for handling organic acids like uric acid and it inhibits the renal reabsorption of uric acid so that it passes into the urine. Probenecid is rapidly absorbed following oral administration and is metabolized by the liver and excreted through the kidneys. Often, probenecid is administered in combination with colchicine, which reduces the blood urate level, while colchicine protects against the onset of an acute gouty attack. Probenecid causes GI disturbances, including nausea and vomiting. It is recommended that it be taken with meals, milk, or antacids to avoid GI upset. Other adverse effects reported with probenecid include arthralgias, skin rash, and fever. To reduce the likelihood of developing renal urate stones, any person taking an antigout drug should drink 10 to 12 eight-ounce glasses of water daily.
Clinical Indications and Preferred Therapy The clinical management of gout, even with diet adjustment, is a life-long process. For the treatment of acute gout attacks, relief of pain, and interruption of the inflammatory process, colchicine and specific NSAIDs (indomethacin, naproxen) and sodium thiosalicylate are indicated. For the treatment of hyperuricemia associated with gout and gouty arthritis, probenecid has been a longstanding drug of choice. Because of its ability to inhibit the renal tubular secretion of most penicillins and cephalosporins, probenecid elevates and prolongs the plasma levels of these antibiotics. Probenecid is therefore also approved for use as an adjunct to antibiotic therapy. Allopurinol is approved for the management of primary and secondary gout, acute gout attacks, tophi, joint destruction, uric acid stones, or nephropathy. Because of its mechanism of action, it also is recommended for reduction of serum and urinary uric acid resulting from the treatment of malignancies, leukemia, and lymphoma. LO 20.5
DRUG INTERACTIONS Nonopioid analgesics and antiinflammatory drugs undergo a variety of drug interactions. The major area of interaction includes drug displacement from protein-binding sites. This displacement usually results in an increased toxicity of the displaced drug. Inhibition of uric acid excretion is the next most frequent drug interaction. Since most of these drugs are weak acids, they compete with uric acid for sites of excretion
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along the renal tubules. This competition, especially low doses of probenecid concurrent with aspirin, may cancel the uricosuric effect desired in the treatment of chronic gout. Of noteworthy importance is the potential for serious interaction with acetaminophen because of its ubiquitous use. The hepatotoxicity associated with acetaminophen may increase with the long-term
use of drugs that induce microsomal enzymes. The concomitant use of acetaminophen with several drugs ranging from alcohol to rifampin is associated with decreased analgesic therapeutic effect to hepatotoxicity. Clinically significant drug interactions among the classes of drugs represented in this chapter are presented in Table 20:5.
Table 20:5
Drug Interactions with the Nonopioid Analgesics and Antigout Drugs Pharmacological agents
Interact with
Response
Acetaminophen
Alcohol, barbiturates, carbamazepine, hydantoins, isoniazid, rifampin
Increased risk of hepatotoxicity
Acetaminophen
Warfarin
Increases anticoagulant effect of warfarin; increases circulating warfarin levels
Allopurinol
Cyclophosphamide
Increased bone marrow depression
Allopurinol
Ampicillin
Skin rash has occurred with concurrent use of these drugs
Allopurinol
Thiazides, ACE inhibitors
Higher risk of hypersensitivity to allopurinol
Aspirin
Antacids, corticosteroids, urinary alkalinizing drugs
Decrease the effects of aspirin (salicylate) by increasing renal excretion, decreasing tubular reabsorption
Aspirin (doses > 2 g/day)
Sulfonylureas, insulin
Potentiate glucose lowering effect; hypoglycemia
Aspirin
Heparin
Increased risk of bleeding
Diflunisal
Indomethacin
Decreased renal clearance of indomethacin; fatal GI hemorrhage has occurred
Febuxostat
Mercaptopurine, azathioprine, theophylline
Increases the blood levels of these drugs by blocking their metabolism via xanthine oxidase
NSAIDs
Alcohol
Increased risk for GI ulceration
NSAIDs
Lithium
May elevate the plasma level of lithium
Indomethacin Oxyphenbutazone Phenylbutazone Salicylates
Anticonvulsants, methotrexate, oral anticoagulants, oral hypoglycemics
Increased bleeding, toxicity due to protein binding, displacement or additive effect of depressing prothrombin
Salicylates
Uricosuric agents
Decreased renal excretion of uric acid
Indomethacin
Furosemide, thiazide diuretics
Decreased sodium excretion and antihypertensive action
Indomethacin
Lithium
May elevate plasma lithium concentrations
Probenecid
Acyclovir, clofibrate, oral hypoglycemics, methotrexate, NSAIDs, penicillins, sulfonamides
Decreases renal excretion, increases plasma concentrations of these drugs
Abbreviations: ACE, angiotensin-converting enzyme.
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LO 20.6
PREFERRED THERAPY For the relief of fever, headaches, pains, and inflammation of any nature, including arthritis, and prophylaxis for prevention of heart attack or stroke, aspirin is still the drug of choice. Because of their availability in OTC products, ibuprofen and naproxen are frequently used to relieve aches, pains, and inflammation. There is no cardio protection associated with any dose of these NSAIDs. Acetaminophen is a preferred drug for reducing fever. In aspirin-sensitive patients or children and teenagers with symptoms of active viral infections or chickenpox, to relieve fever, acetaminophen may be the appropriate drug.
Acetaminophen is not an antiinflammatory drug. The NSAIDs are primarily used to treat inflammatory conditions, notably those associated with arthritis. The condition of the patient and the status of the inflammatory condition to be treated will determine which NSAID is selected. Treatment for acute gout attacks is colchicine. If hyperuricemia is the trigger for the gout, the drugs of choice to block the production of uric acid are allopurinol and febuxostat. For prophylactic treatment of gout through increased urinary excretion of uric acid, probenecid is warranted. In many patients, a combination of colchicine and probenecid or allopurinol may be needed to bridge management of the acute attack while the uric acid is being processed.
Patient Administration and Monitoring The drugs in this class are so widely available as OTC preparations and are used by such a broad group of patients that there is more opportunity for inappropriate use to occur. Children and the elderly may be more susceptible to inappropriate exposure, in part, because the drugs are not seen as harmful—that is, as strong, serious medications. After all, prescriptions are not required for the vast majority of the preparations. Therefore, patients benefit from an opportunity to hear clear instruction about the use of these drugs.
Patient Instructions Whether the active analgesic or antiinflammatory is OTC or prescription, the potential for adverse effects to occur increases with dose and chronic use. Explain to patients that too frequent readministration of OTC preparations can equal the mg amount available by prescription. Patients should be clearly instructed to take solid oral formulations with a full glass of water to avoid the possibility of the pill or capsule lodging in the esophagus. Probenecid and allopurinol must be accompanied by 10 to 12 full glasses of water daily in order to maintain a neutral to slightly alkaline urine and prevent the formation of kidney stones. Large doses of vitamin C may acidify the urine and increase the potential for kidney stone formation. Patients may be told that GI irritation can be reduced by taking the medication with milk or with meals. Sustainedrelease formulations should not be crushed or chewed because more drug is delivered earlier than the formulation intended.
Notify the Physician With any of the analgesic, antiinflammatory drugs, the patient should call the doctor if fever continues more than
3 days, if pain persists more than 5 days, or if redness or swelling develops. Severe or recurrent pain, or high or continued fever, may indicate serious illness requiring medical attention. With any of these drugs, the patient should notify the doctor if ringing in the ears (tinnitus), dizziness, hearing impairment, or dimmed vision occurs and discontinue the medication as directed. Bronchospasm and/or rhinitis may indicate the development of aspirin intolerance. The physician should be notified for further evaluation. Patients with acute asthma, urticaria, and nasal polyps should avoid aspirin and NSAIDs. These drugs may cause drowsiness that will reduce the coordination and attention required for driving, operating machinery, or performing tasks requiring manual dexterity. Elderly patients should not exceed the recommended daily doses of NSAIDs; this includes exposure to OTC preparations while taking prescribed NSAIDs.
Special Caution with Aspirin and Acetaminophen Aspirin, alcohol, and alcohol-containing products should be avoided during NSAID therapy. When possible, aspirin should be avoided 1 week prior to surgery because of the possibility of postoperative bleeding. Standard procedure for discontinuation of aspirin and NSAIDs prior to surgery may vary from 5 to 10 days in different institutions. Patients allergic to tartrazine dye should avoid aspirin. Acetaminophen should be used at the lowest effective dose for the shortest period necessary in patients who take warfarin. Coagulation status, INR, should be monitored
(Continued)
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more frequently in these patients while they are taking acetaminophen. Patients should be educated to read the active ingredients for all over-the-counter medication before they take the cold, headache, or analgesic medication to be sure additional acetaminophen does not impact their current anticoagulant therapy. If the patient is in doubt about the possible ingredient, he or she should be instructed to call the doctor, nurse, or pharmacist to confirm the safety of taking the additional medication.
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Use in Pregnancy All of these drugs are designated Food and Drug Administration (FDA) Pregnancy Category B or C except for aspirin (D). Aspirin causes effects in the mother, including anemia, bleeding, and delayed labor. Since salicylates cross the placenta, prostaglandin synthesis in the fetus may be suppressed. The recommendation is to avoid salicylates during pregnancy, especially during the third trimester. Acetaminophen is the alternative analgesic at all stages of pregnancy. It appears safe for short-term use.
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Chapter Review Understanding Terminology Answer the following questions. 1. How do the nonopioid analgesics differ from the opioid analgesics? (LO 20.1, 20.2) 2. Define analgesia. (LO 20.1) 3. Explain the term inflammation. (LO 20.1) Match the description in the left column with the appropriate term in the right column. ___ 4. Joint pain. (LO 20.1, 20.2)
a. arthralgia
___ 5. Pain associated with muscle injury. (LO 20.1, 20.2)
b. arthritis
___ 6. Inflammation of the joints. (LO 20.1, 20.2)
c. dysmenorrhea
___ 7. Small area of skin or mucous membrane that is discolored because of localized hemorrhages. (LO 20.5)
d. myalgia
___ 8. Condition in which pain and inflammation of joints are accompanied by elevated body temperature. (LO 20.1, 20.2)
f. rheumatic fever
e. petechia
g. salicylism
___ 9. Painful menstruation. (LO 20.1) ___ 10. Condition in which toxic doses of salicylates result in nausea, tinnitus, and delirium. (LO 20.5)
Acquiring Knowledge Answer the following questions. 1. What are the three major pharmacological effects produced by the salicylates? (LO 20.3) 2. How do the nonopioid analgesics relieve pain? (LO 20.1) 3. Why do some people experience nausea and vomiting after taking aspirin? (LO 20.5) 4. Why do the salicylates potentiate the action of the oral anticoagulant drugs? (LO 20.4) 5. What physiological changes might occur during acute salicylate toxicity? (LO 20.5) 6. Why is acetaminophen recommended for patients who are aspirin sensitive? (LO 20.3) 7. How do antiinflammatory drugs interrupt the process of inflammation? (LO 20.1) 8. Which antiinflammatory drugs should not be administered over long periods of time (such as 2 months)? (LO 20.5) 9. What metabolic imbalance is associated with the production of gout? (LO 20.6) 10. How does colchicine alleviate the acute inflammatory reaction of gout? (LO 20.6) 11. How do allopurinol and probenecid differ in their antigout mechanism of action? (LO 20.6)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. Assume that you work in an emergency room of a hospital. For each of the following patients who come to the ER tonight with a nonopioid drug overdose, determine the probable drug and what should be done to treat the overdose. a. Patient A presents with respiratory acidosis, low blood and urine pH values, profuse sweating, vasodilation, and hypotension. (LO 20.5)
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Chapter Review Continued b. Patient B presents with nausea and vomiting. Liver enzymes (AST, ALT, bilirubin, and thrombin) are all high and rising. Liver damage seems imminent. (LO 20.5) 2. For each of the following adult patients, how much nonopioid analgesic drug is required to produce the desired effect? a. Patient A wants to take aspirin to relieve the fever, aches, and pains of the flu. (LO 20.3) b. Patient B wants to take aspirin as an antiinflammatory agent for osteoarthritis. (LO 20.4) c. Patient C wants to take ibuprofen for dysmenorrhea. (LO 20.4) d. Patient D wants to take ibuprofen for osteoarthritis inflammation. (LO 20.4) e. Patient E wants to take naproxen for menstrual pain. (LO 20.4) f. Patient F wants to take naproxen for inflammation associated with rheumatoid arthritis. (LO 20.4) 3. A mother of a 26-month-old child calls. Her child is coughing, has nasal congestion, and is running a fever. She would like to know how much aspirin she should give her child. The child weighs 22 pounds. (LO 20.3) 4. John is 62 years old and is currently taking Coumadin, Tenormin, and Micronase. He wants to know if he can take Anacin for his headache. (LO 20.5) 5. Your office receives a frantic call from a young mother. Her 1-1/2 year old accidentally got ahold of children’s chewable Tylenol. She is not sure how many she ate, but thinks there were at least 20 tablets in the bottle, and now it is empty. She feels that her daughter must have gotten into this within the last 1-1/2 hours. What should she do? (LO 20.5)
Multiple Choice Use your critical-thinking skills to answer the following questions. 1. Which of the following is pharmacologically considered an all-around antiinflammatory drug? (LO 20.3, 20.5) A. febuxostat B. allopurinol C. ibuprophen D. probenecid 2. Cyclooxygenase (COX) is a family of enzymes that (LO 20.1, 20.3) A. increase uric acid production and deposition B. make various prostaglandins from arachidonic acid C. metabolize NSAIDs D. are inhibited by allopurinol and febuxostat 3. Which of the following is correct about NSAIDs? (LO 20.1, 20.5) A. they are a large class of antiinflammatory drugs that inhibit more than one type of cyclooxygenase (COX-1, 2) B. there are no gastrointestinal side effects associated with this group of drugs C. the class includes cortisone D. there is no association with gastrointestinal bleeding with chronic use of these drugs 4. Acetaminophen (LO 20.1, 20.3) A. is an aspirin substitute for the management of severe arthritis B. is an aspirin substitute for analgesia and antipyresis in aspirin-sensitive patients C. has no associated liver toxicity with chronic use of large doses (> 4 g/day) D. is not given to children because it causes flu-like symptoms
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5. NSAIDs are (LO 20.2, 20.4) A. represented by probenecid B. used for the clinical management of hyperprostaglandinemia C. not to be used in the management of rheumatoid arthritis D. highly bound to plasma proteins 6. Which of the following is correct? (LO 20.4, 20.5) A. gout is a condition of oxalate crystal deposition in the joints B. uricosuric drugs can be given with hypouricemic drugs to lower uric acid concentrations C. aspirin never causes petechial hemorrhages D. COX-2 inhibitors (celecoxib) have greater antiplatelet activity than aspirin and NSAIDs 7. The COX-2 selective NSAID celecoxib (Celebrex) (LO 20.1, 20.4, 20.5) A. produces more effective analgesia than older NSAIDs B. is used for its effectiveness in relieving minor headache C. inhibits xanthine oxidase to relieve pain and inflammation D. is primarily an antiinflammatory drug 8. Antiinflammatory drugs (LO 20.2, 20.3, 20.4) A. include acetaminophen B. vary in their ability to reduce all types of inflammation C. have no effect on uterine contraction or vasoconstriction associated with dysmenorrhea D. do not require special cautionary warnings about likely adverse effects with their use
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Select all of the following that are part of the inflammatory process. (LO 20.1) A. prostaglandins are released B. phagocytes migrate to area C. vasodilation D. proteins leak out of injured cells 2. Under which circumstances would nonopioid drugs be the appropriate treatment? (LO 20.2) A. for pain from broken bones B. in the elderly with moderate to severe pain C. for treatment of pain from cancer D. for acute postoperative pain 3. Which of the following is not a reason to choose acetaminophen? (LO 20.3) A. for aspirin-sensitive patients B. for low GI irritation C. for its antiinflammatory effects D. for its anticoagulant properties 4. Choose the reasons why probenecid is useful in treating gout. (LO 20.6) A. enhances the renal excretion of uric acid B. decreases the uric acid clearance from the blood C. increases reabsorption of uric acid D. alters the formation of uric acid
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Chapter Review Continued 5. Select the indications for aspirin. (LO 20.2) A. analgesia B. antipyresis C. anticoagulation D. dysmenorrhea
Sequencing Place the following in order of gouty attack and colchicine’s mechanism of action to alleviate symptoms. (LO 20.6) _______________
_______________
_______________
_______________
First
_______________ Last
pH of joint does not fall increase in uric acid levels uric acid crystals accumulate in joint fluid phagocytes enter joint phagocytes unable to attack uric acid crystals
Classification Place the following drugs into the appropriate category. (LO 20.1, 20.6) allopurinol
ibuprofen
colchicine
indomethacin
etodolac
naproxen
febuxostat
probenecid
Gout treatments
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Nonsteroidal antiinflammatories
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Labeling Label the structures indicated. (LO 20.1)
Splinter
From damaged tissue 1
Bacteria From mast cells
5
From blood
4
Increased permeability
Mast cells
3 Neutrophils
2 Blood capillary or venule Inflammatory response
For interactive animations, videos, and assessment, visit:
www.mcgrawhillconnect.com Chapter 20 • Chapter Review
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PART
4 Pharmacology of the Heart CHAPTER 21 Review of Cardiac Physiology and Pathology 322
CHAPTER 22 Treatment of Heart Failure 331
CHAPTER 23 Antiarrhythmic Drugs 347
CHAPTER 24 Antianginal Drugs 363
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Chapter 21
Review of Cardiac Physiology and Pathology
KEY TERMS angina pectoris: chest pain caused by insufficient blood flow to the heart. arteriosclerosis: hardening or fibrosis of the arteries. atherosclerosis: accumulation of fatty deposits in the walls of arteries. AV: atrioventricular, as in the AV node. chronic heart failure (CHF): heart disease caused by weakness of the contractile force of the myocardium. conduction system: specialized cardiac tissue that transmits electrical impulses and regulates the activity of the heart. coronary artery disease (CAD): disease of the coronary arteries that decreases blood flow to the heart. depolarization: the decrease in electrical potential across a cell membrane that results in excitation and generation of an action potential. electrocardiogram (ECG): recording of the electrical activity of the heart. ischemia: condition of insufficient tissue blood flow. myocardial infarction (MI): sudden death of an area of heart muscle, commonly referred to as a heart attack. myocardium: the muscular layer of the heart. repolarization: return of the electrical potential across a cell membrane to its resting state following depolarization. SA: sinoatrial, as in the SA node.
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Learning Outcomes
After studying this chapter, you should be able to 21.1 describe the normal flow of blood through the chambers and blood vessels of the heart. 21.2 identify the different parts of the conduction system and how the flow of electrical impulses coordinates contraction of the cardiac chambers.
21.4 recognize the different wave forms of the ECG and how they relate to the electrical activity of the heart. 21.5 identify the clinical features of chronic heart failure (CHF), coronary artery disease (CAD), and myocardial infarction (MI).
21.3 explain autonomic nervous system regulation of the heart.
Introduction
The circulatory system is responsible for supplying blood flow to all the tissues and organs of the body. The heart is a muscular organ whose main function is to generate the force that pumps the blood through the circulatory system. The heart is composed of four muscular chambers, two atria and two ventricles. Contraction of cardiac muscle, the myocardium, generates the arterial blood pressure, which is necessary to distribute blood throughout the body. Blood flow to the heart itself is supplied by the coronary arteries, which branch off the aorta immediately after leaving the heart. Within the walls of the heart are specialized cells that make up the conduction system. The function of the conduction system is to coordinate the contractions of the atria and ventricles. There are a number of disease conditions that can affect the function of the myocardium, conduction system, and coronary arteries. These diseases, chronic heart failure (CHF), coronary artery disease (CAD), and myocardial infarction (MI), are among the leading causes of death in this country.
LO 21.1 1
LO 21.2 2
LO 21.3 3
LO 21.4
CARDIAC F UNCTION To understand cardiac physiology, it is convenient to divide the heart into three functional parts: cardiac muscle, conduction system, and nerve supply.
Cardiac Muscle The pumping ability of the heart is due to the arrangement of heart muscle (myocardium) into a system of four chambers. Contraction of the chambers increases pressure within the ventricles and forces the blood through a system of valves and blood vessels. The superior and inferior venae cavae receive all the venous blood from the body and drain it into the right atrium. The blood then passes through the tricuspid valve into the right ventricle. The right ventricle pumps the blood through the pulmonary arteries to the lungs, where it gets oxygenated. From the lungs the blood passes through the pulmonary veins back to the left atrium.
Blood then passes through the bicuspid valve into the left ventricle. The left ventricle pumps the blood out of the heart into the aorta, where it then gets distributed to the rest of the body. The path of blood flow is shown in Figure 21.1. The blood supply to the myocardium is through the coronary arteries that branch off the aorta immediately after the aorta leaves the heart. Under normal conditions, blood flow in the coronary arteries is dependent upon the force of myocardial contraction. Any interference with the normal function of the myocardium or with the normal flow of blood to the myocardium results in ischemia and a decreased capacity of the heart to contract.
Conduction System The conduction system of the heart is composed of a specialized type of nervous tissue that is located in specific areas of the heart. The conduction system is shown in Chapter 21 • Review of Cardiac Physiology and Pathology
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Description of Blood Flow through the Heart
Figure 21.1
1 Blood enters right atrium from superior and inferior venae cavae. 10
2 Blood in right atrium flows through right AV valve into right ventricle.
Aorta
Left pulmonary artery
11 5
5 9
Superior vena cava Right pulmonary veins
Pulmonary trunk 4
Left pulmonary veins
6
6
Left atrium Aortic valve
1 7
3
Right atrium
Left AV (bicuspid) valve
8
Right AV (tricuspid) valve Right ventricle Inferior 11 vena cava
Left ventricle
2
3 Contraction of right ventricle forces pulmonary valve open. 4 Blood flows through pulmonary valve into pulmonary trunk. 5 Blood is distributed by right and left pulmonary arteries to the lungs, where it unloads CO2 and loads O2. 6 Blood returns from lungs via pulmonary veins to left atrium. 7 Blood in left atrium flows through left AV valve into left ventricle. 8 Contraction of left ventricle (simultaneous with step 3 ) forces aortic valve open. 9 Blood flows through aortic valve into ascending aorta. 10 Blood in aorta is distributed to every organ in the body, where it unloads O2 and loads CO2. 11 Blood returns to heart via venae cavae.
Description of the Cardiac Conduction System and Transmission of an Electrical Impulse
Figure 21.2
1 SA node fires.
Right atrium
2 Excitation spreads through atrial myocardium.
2
1
Sinoatrial node (pacemaker)
Left atrium 2
Atrioventricular node Atrioventricular bundle
Purkinje fibers
3
Bundle branches 4
5
3 AV node fires.
4 Excitation spreads down AV bundle. 5 Purkinje fibers distribute excitation through ventricular myocardium.
Purkinje fibers
Figure 21.2. Conduction tissue has a unique property known as autorhythmicity. This property enables the heart to initiate its own electrical stimulation. Normally, an 324
electrical impulse is generated within the sinoatrial (SA) node, referred to as the pacemaker. This impulse continues through both atria to the atrioventricular (AV)
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Figure 21.3
Electrocardiogram Recording from Lead II
5 mm = 0.5 mV
5 mm = 0.2 sec = 200 msec
Voltage (10 mm/mV)
R
PR Segment
ST Segment
P
T
Q PR Interval
ST Interval S
QT Interval
QRS Interval Paper speed 25 mm/sec Time The recording shows ECG waves, segments, intervals, and standard calibrations for time and voltage.
node. The AV node transmits the impulse down through the AV bundle (bundle of His) and through the left and right bundle branches and Purkinje fibers. This impulse conduction results in electrical excitation and subsequent contraction of both atria, followed by excitation and contraction of both ventricles. Consequently, the contractions of both sides of the heart are coordinated by the conduction system and each side pumps the same amount of blood at the same time. A recording of the electrical activity of the heart results in a characteristic waveform known as the electrocardiogram (ECG). An ECG records the electrical activity of the heart from 12 different body locations or leads. Each lead position provides a different electrical view of the heart. This is important for detecting abnormalities and cardiac arrhythmias. The pattern of the ECG reflects depolarization and repolarization of cardiac tissue. Depolarization of the atria produces the P wave of the ECG. The PR interval, measured from the beginning of the P wave to the beginning of the R wave,
is the time required for passage of an electrical impulse from the SA node through the AV node. Depolarization of the ventricles produces the QRS wave (AV node through Purkinje fibers). Repolarization of the ventricles is represented by the T wave. The QT interval represents the time required for both depolarization and repolarization of the ventricles. Figure 21.3 illustrates the normal wave forms, intervals, and segments recorded from Lead II of the electrocardiogram. Normal values have been established for the different wave forms and intervals and measurements outside of the normal ranges suggest disturbances of conduction.
Nerve Supply The heart receives its nerve supply from both divisions of the autonomic nervous system. Since the heart possesses the ability to initiate its own heartbeat, the function of the autonomic nervous system is to regulate the rate and force of contraction of the heart. Sympathetic nerves release norepinephrine at adrenergic nerve Chapter 21 • Review of Cardiac Physiology and Pathology
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endings that go to the SA node (increase heart rate), AV node (increase AV conduction), and myocardium (increase contractility). Sympathetic nerves become active when the body needs to expend energy and during the “fight or flight” reaction (Chapter 5). Parasympathetic nerves release acetylcholine at cholinergic nerve endings that go to the SA node (decrease heart rate) and AV node (decrease AV conduction). The parasympathetic system has little effect on myocardial contraction. Parasympathetic nerves become active when the body is restoring energy during eating, digestion, sleep, and elimination of urinary and intestinal waste products. LO 21.5
M AIN D ISEASES OF THE H EART Chronic Heart Failure (CHF) In CHF, the contractile ability of the heart to pump blood is decreased so that the heart pumps out less blood than it receives. Blood accumulates inside the chambers, causing enlargement (dilatation) of the heart. Consequently, there is less blood circulating in the blood vessels to supply the body organs. The kidneys— particularly sensitive to a decrease in blood flow— respond by retaining more water and electrolytes, leading to fluid retention and edema. When the left side of the heart fails, fluid accumulates in the lungs (pulmonary edema) and interferes with gas exchange, resulting in shortness of breath. When the right side fails, fluid accumulates in the abdominal organs (ascites) and lower extremities. Failure in one side of the heart is usually followed by failure of the other side, resulting in total heart failure. Heart failure is treated with diuretics, vasodilators, beta blockers, and cardiac glycosides (Chapter 22).
Coronary Artery Disease Coronary artery disease (CAD) is a general term for several cardiac conditions. An insufficient flow of blood through the coronary arteries to the heart is a common factor in arteriosclerosis, atherosclerosis, and angina pectoris. These disease conditions are the major contributors to development of a myocardial infarction.
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Arteriosclerosis Arteriosclerosis is a disease of the aging process in which there is a hardening (fibrosis) and narrowing of the arteries. These changes result in a decreased blood flow. One type of arteriosclerosis, in which fatty deposits (plaques) accumulate within the walls of the arteries, is known as atherosclerosis. Atherosclerosis is primarily caused by abnormally high cholesterol levels in the blood. Cholesterol forms the fatty deposits (plaque) that decrease blood flow. The coronary arteries are particularly prone to both conditions and, as stated earlier, any abnormal decrease in coronary blood flow decreases the function of the heart.
Angina Pectoris Angina pectoris refers to the clinical condition characterized by chest pain caused by insufficient coronary blood flow. Arteriosclerosis, atherosclerosis, and coronary artery spasms are the major causes of angina pectoris. Attacks of angina, usually caused by physical exertion or psychological stress, are relieved by rest and a class of drugs known as the antianginal drugs (Chapter 24).
Myocardial Infarction A myocardial infarction or MI occurs when an area of heart muscle is deprived of blood flow. The area deprived of blood dies unless immediate treatment is administered to restore blood flow. Blockage of blood flow is caused by the formation of a blood clot in one of the coronary arteries. The clot usually forms in a vessel where there are atherosclerotic plaques. Anticoagulant and fibrinolytic drugs (Chapter 27) can be administered to dissolve the clot and prevent further blockage. Large infarcts usually result in sudden death, whereas lesser infarcts undergo a healing process in which the dead muscle cells are replaced by connective tissue. Consequently, after an attack, the amount of contractile tissue of the heart is reduced. Secondary complications commonly involve the development of heart failure and disturbances of the conduction system (cardiac arrhythmias). Treatment for a myocardial infarction is aimed at allowing the heart to rest and undergo its normal healing process while treating any complications. Patients then undergo a period of physical rehabilitation and exercise to strengthen the heart and improve cardiovascular conditioning.
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Chapter Review Understanding Terminology Answer the following questions. 1. What is the difference between angina pectoris and myocardial infarction? (LO 21.5) 2. What do the following abbreviations stand for: AV, CAD, CHF, ECG, SA? (LO 21.2, 21.4, 21.5) 3. Differentiate between arteriosclerosis and atherosclerosis. (LO 21.5)
Acquiring Knowledge Answer the following questions. 1. Describe the path of blood flow through the cardiac chambers. Which ventricle forces the blood into the general circulation (aorta)? (LO 21.1) 2. How is the blood supplied to the myocardium? (LO 21.1) 3. What makes the cardiac conduction system unique? Where is the conduction system located? (LO 21.2) 4. Describe the path of an electrical impulse that is generated at the SA node. (LO 21.2) 5. Name the characteristic parts of a normal ECG. What can an ECG tell you about cardiac functions? (LO 21.2) 6. What would a lengthened PR interval indicate? What does a widened QRS complex suggest? (LO 21.2) 7. How do the divisions of the autonomic nervous system (ANS) affect cardiac function? (LO 21.3) 8. How might congestive heart failure affect the function of the heart? (LO 21.5) 9. How can coronary heart disease contribute to the development of a myocardial infarction? (LO 21.5)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. A patient is brought into the emergency room in a collapsed state. She has shortness of breath, low blood pressure, and is making a gurgling sound with each breath. What is your preliminary diagnosis? (LO 21.5) 2. During a scheduled office visit Mrs. Jones explains that after she climbs stairs she has to sit down and rest for a while. One day last week when there was no place to sit, she felt some pain and discomfort in her chest. What condition is most likely causing these symptoms? (LO 21.5) 3. Your grandfather is complaining of extreme weakness and fatigue. You notice that his ankles are swollen and that he can’t put his shoes on. What cardiac condition is associated with peripheral edema? (LO 21.5) 4. Mr. Smith’s pulse is irregular and a subsequent ECG reveals that his QRS waves have an abnormal appearance and the T wave is inverted. What part of the heart do you think is affected? (LO 21.5) 5. The rescue squad brings in a patient who is complaining of a sharp pain radiating down his left arm. He is extremely fatigued, is short of breath, and has a very rapid heart rate. The ECG records a serious cardiac arrythmia. What cardiac condition causes these symptoms? (LO 21.5)
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Chapter Review Continued Multiple Choice Use your critical-thinking skills to answer the following questions. 1. Select the direction of normal blood flow that is correct. (LO 21.1) A. left ventricle to pulmonary artery B. left atrium to pulmonary veins C. left ventricle to aorta D. right ventricle to pulmonary veins 2. The QRS wave on the ECG represents (LO 21.4) A. depolarization of the atria B. depolarization of the ventricles C. repolarization of the atria D. repolarization of the ventricles 3. Increased heart rate is caused by (LO 21.3) A. sympathetic stimulation of the SA node B. parasympathetic stimulation of the ventricles C. sympathetic stimulation of the ventricles D. parasympathetic stimulation of the SA node 4. Angina pectoris can be caused by (LO 21.5) A. arteriosclerosis B. atherosclerosis C. coronary artery spasm D. all statements are true 5. Select the true statement(s) concerning the conduction system. (LO 21.2) A. the SA node is located in the wall of the right atrium B. the Purkinje fibers are located in the atria C. the AV node is located between the atria and ventricles D. only A and C are true
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Select all of the following that apply to the cardiac conduction tissue. (LO 21.2) A. it is nervous tissue B. its electrical impulse is recorded on an EEG C. it requires outside stimulation D. it has autorhythmicity 2. The functions of the sympathetic nervous system in heart activity include (LO 21.3) A. increases in heart rate B. increased AV conduction C. increased contractility D. increased vasoconstriction 3. Which of the following is true of an electrocardiogram? (LO 21.4) A. the P wave is measuring the repolarization of the atria B. the PR interval measures the time of impulse passage from SA node through the AV node C. the QRS wave is measuring the depolarization of the ventricles D. the QT wave represents the repolarization of the ventricles and Purkinje fibers
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4. Choose the clinical features of chronic heart failure. (LO 21.5) A. hardening of the arteries B. fatty deposits in the arteries C. blood accumulation in the heart D. fluid retention 5. Which of the following are indications of a myocardial infarction? (LO 21.5) A. decreased blood flow to heart muscle B. area of dead heart tissue C. development of scar tissue in the heart D. cardiac arrhythmias
Sequencing Place the following in order of which is touched first as blood flows through the heart. (LO 21.1) ______________
______________
______________
______________
First
______________ Last
bicuspid valve right atrium tricuspid valve left atrium right ventricle
Classification Place the following symptoms into the appropriate category. (LO 21.1) hardening of the arteries
decrease in overall blood circulation
enlargement of the heart
decreased contractile ability of the heart
decrease in coronary blood flow
plaque deposits in arteries
CHF
CAD
Matching Match the following terms with the correct definitions. (LO 21.5) a. angina pectoris e. chronic heart failure b. arteriosclerosis f. ischemia c. atherosclerosis g. myocardial infarction d. coronary artery disease 1. 2. 3. 4. 5. 6. 7.
___ ___ ___ ___ ___ ___ ___
accumulation of fatty deposits in the walls of arteries sudden death of an area of heart muscle disease of the coronary arteries that decreases blood flow to the heart condition of insufficient tissue blood flow heart disease caused by weakness of the contractile force of the myocardium chest pain caused by insufficient blood flow to the heart hardening of the arteries Chapter 21 • Chapter Review
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Chapter Review Continued Labeling Fill in the missing labels. (LO 21.2)
2
1
2 3
4
5
For interactive animations, videos, and assessment, visit:
www.mcgrawhillconnect.com 330
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Chapter 22
Treatment of Heart Failure DRUG CLASS AT A GLANCE OTC
NO
PRESCRIPTION
YES
SCHEDULED DRUGS NO FDA PREGNANCY CATEGORY
INDICATIONS Chronic heart failure
B, C, D— ACEIs, ARBs
KEY TERMS afterload: a measure of the vascular resistance that the left ventricle must overcome in order to eject blood during contraction. cardiac glycoside: drug obtained from plants of the genus Digitalis. cardiac output (CO): the amount of blood pumped per minute by the heart. chronic heart failure (CHF): condition in which the heart is unable to pump sufficient blood to the tissues of the body. digitalization: method of dosage with cardiac glycosides that rapidly produces effective drug levels. ectopic beat: extra heartbeat, a type of cardiac arrhythmia. hypercalcemia: high serum calcium. hyperkalemia: high serum potassium. hypokalemia: low serum potassium. maintenance dose: daily dosage of cardiac glycoside that maintains effective drug levels in the blood. Na/K adenosine triphosphatase (Na/K ATPase): enzyme that energizes the sodium/potassium pump and is inhibited by cardiac glycosides. preload: refers to venous return, the amount of blood returning to the heart that must be pumped.
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Learning Outcomes
After studying this chapter, you should be able to
mechanisms of action of the different types of vasodilator drugs.
22.1 describe the symptoms of chronic heart failure and understand the compensatory activation of the sympathetic nervous system and the reninangiotensin-aldosterone mechanism.
22.4 explain the use of beta adrenergic blockers in the treatment of CHF.
22.2 recognize the mechanisms of action and uses of diuretics in CHF.
22.5 describe the mechanism of action of digoxin and list the adverse effects and potentially serious toxicities of this drug.
22.3 describe how vasodilator drugs reduce preload and afterload and understand the
Introduction
Heart failure occurs when the heart is unable to pump sufficient blood to the tissues of the body. The main causes of heart failure are untreated hypertension, myocardial infarction (MI), valvular defects, and other conditions that weaken the contractile force of the heart. Blood accumulates in the heart and subsequently backs up into the lungs and large veins. This causes dilation of the heart, pulmonary edema, and peripheral edema of the lower extremities. The accumulation of blood in the heart, lungs, and tissues is referred to as congestion. When the heart is in failure, the cardiac output (CO), the amount of blood pumped by the heart per minute, is significantly reduced. This in turn causes a reduction in blood pressure. The result is that the cardiovascular system is unable to meet the demands of the body for blood flow and delivery of oxygen. Heart failure is a chronic disease and commonly referred to as CHF, chronic heart failure. Individuals with CHF display the following symptoms: tiredness, fatigue, shortness of breath, rapid heartbeat, and pulmonary and peripheral edema. The treatment of CHF involves the use of several different drug classes that include the diuretics, vasodilators, beta blockers, and the cardiac glycoside digoxin. Two or more drugs may be required to effectively treat CHF.
LO 22.1
CHRONIC HEART FAILURE (CHF) Chronic heart failure is described as a failure of the heart to adequately pump enough blood to supply the tissues and organs of the body with oxygen and other nutrients. In untreated CHF there are compensatory mechanisms that are activated by the body that attempt to overcome the heart failure. Cardiac muscle undergoes hypertrophy, where the walls of the heart chambers increase in size and undergo structural remodeling in an attempt to generate more forceful contractions. In addition, neurohumoral compensatory reflexes involving the sympathetic nervous system and kidneys are activated (Figure 22.1). 332
Sympathetic activation stimulates the release of norepinephrine and epinephrine from adrenergic nerves and the adrenal medulla. This produces vasoconstriction (alpha-1 effect), increased heart rate, and force of myocardial contraction (beta-1 effects). These actions are an attempt by the body to increase blood pressure and increase cardiac output. The kidneys respond by releasing a substance called renin. Renin stimulates the enzymatic conversion of a precursor protein from the liver, angiotensinogen, to angiotensin I. An enzyme produced by the lungs, angiotensin-converting enzyme (ACE), converts angiotensin I into angiotensin II. Angiotensin II is a potent vasoconstrictor and also stimulates the release of aldosterone from the adrenal cortex and antidiuretic
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Figure 22.1
Compensatory Responses That Are Activated by the Decrease in Cardiac Output and Blood Pressure during Heart Failure Cardiac output
Blood pressure
Renal blood flow
Sympathetic discharge
Renin release
Angiotensin ll
Force
Rate
Cardiac output (via compensation)
Vasoconstriction
ADH
Aldosterone
Sympathetic activation increases heart rate, force of contraction, and vasoconstriction. Release of renin leads to the formation of angiotensin II, which causes vasoconstriction, and the release of both aldosterone and antidiuretic hormone (ADH).
hormone (ADH) from the hypothalamus and pituitary gland. This sequence of actions is referred to as the renin-angiotensin-aldosterone (RAA) mechanism (Figure 22.2). Aldosterone is a hormone that causes retention of sodium by the kidneys and ADH acts on the hypothalamus to stimulate thirst and on the kidney tubules to retain water. These actions attempt to increase blood volume and blood pressure. Unfortunately the compensatory responses do not usually reverse heart failure. Over time, these compensatory mechanisms cause “remodeling” of the heart, where the heart enlarges (hypertrophy) and becomes weaker and less efficient. The treatment of CHF has evolved over the years away from the use of drugs such as the cardiac glycosides (also referred to as digitalis glycosides) that stimulate myocardial contraction to other drugs such as the vasodilators that relax vascular smooth muscle. Vasodilator drugs increase cardiac output by dilating blood vessels,
which reduces the workload on the heart. Vasodilators that primarily dilate veins and decrease venous return are said to decrease preload. Preload is the amount of blood returning to the heart (venous return). Vasodilators that dilate arteries reduce blood pressure and peripheral resistance and are said to decrease afterload. Afterload is the force (force of ventricular contraction) that the heart must generate in order to overcome vascular resistance (open the aortic valve) and eject blood out of the left ventricle. Decreasing preload, afterload, or both decreases the workload of the heart (volume of blood the heart must pump) and allows the heart to contract more efficiently. This increases cardiac output in CHF and is the main therapeutic effect of vasodilator drugs. Diuretics have always been very useful in CHF and primarily prevent the retention and accumulation of fluid that is the cause of edema and congestion. Beta blockers reduce the heart rate and sympathetic Chapter 22 • Treatment of Heart Failure
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activation, which is usually excessive in CHF. Digoxin is the only cardiac glycoside still available in the United States. Digoxin is now considered a second-line drug and may be added to diuretics and vasodilator drugs when additional myocardial stimulation is required.
Renin-Angiotensin-Aldosterone (RAA) Mechanism
Figure 22.2
Drop in blood pressure
Liver
LO 22.2
DIURETIC THERAPY OF CHF Diuretics are widely used in the treatment of CHF. The main therapeutic effect produced by diuretics is the elimination of excess sodium and water by the kidneys. Sodium and water retention are the main cause of edema and congestion in CHF. The excretion of sodium also produces a vasodilating effect, which also can contribute to the therapeutic effect. There are three different types of diuretics used in CHF: the thiazides, organic acids (loop diuretics), and aldosterone antagonists ( Table 22:1). The thiazide and thiazide-like diuretics are similarly acting drugs that block the reabsorption of sodium in the distal tubules of the kidney nephrons. The potency of these diuretics is considered moderate and they are most effective in mild to moderate CHF in patients with normal renal function. Thiazides increase the excretion of sodium, but they also cause the loss of potassium and can cause hypokalemia. The main difference among the thiazides is the potency, which determines dosage, and the duration of action. The organic acids are commonly referred to as the loop diuretics because the site of diuretic action in kidney nephrons is the thick ascending limb of the loop of Henle. Loop diuretics are the most potent diuretics and primarily indicated for patients with impaired renal function or severe heart failure. Like the thiazides, these diuretics increase the excretion of sodium and water and also cause loss of potassium. Loop diuretics can be administered intravenously in acute heart failure to rapidly relieve edema and pulmonary congestion. Furosemide (Lasix), bumetanide (Bumex), and torsemide (Demadex) are the most widely used loop diuretics and indicated when a more potent diuretic effect is required. The duration of action of these drugs averages 4 to 8 hours. 334
Angiotensinogen (453 amino acids long) Renin
Kidney
Angiotensin I (10 amino acids long) Angiotensinconverting enzyme (ACE)
Hypothalamus
Angiotensin II (8 amino acids long)
Lungs
Cardiovascular system
Adrenal cortex
Aldosterone
ADH
Kidney Vasoconstriction
Sodium and water retention
Thirst and drinking Elevated blood pressure
A drop in systemic blood pressure or a decrease in renal blood flow stimulates the release of renin from the kidneys. In the blood, renin initiates enzymatic reactions that lead to the formation of angiotensin II. Angiotensin II causes vasoconstriction and the release of aldosterone (sodium retention) and ADH (water retention). These actions normally function to maintain normal blood pressure and blood volume. In CHF, there is excessive activation of the RAA mechanism. Drugs that reduce the actions of the RAA mechanism, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are used to treat CHF.
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The aldosterone antagonists Table 22:1 are weak diuretics that act on the collecting ducts of the nephron. Aldosterone is a steroid from the Diuretics Used in Heart Failure adrenal cortex that normally causes the retention of sodium ions and Drug (Trade Name) Duration of action (hrs) excretion of potassium ions. The Thiazides main effects of the aldosterone antagonists are to increase excre6–12 Chlorothiazide (Diuril, Diuregen) tion of sodium and cause retention of potassium. In CHF there can be 6–12 Hydrochlorothiazide (HydroDIURIL) excessive activity of aldosterone and studies have shown that treatment Methyclothiazide (Enduron, Aquatensen) 24 with these drugs reduces mortality. Spironolactone (Aldactone) is a Thiazide-like diuretics competitive antagonist of the aldosterone receptor and is only effecChlorthalidone (Hygroton) 24–72 tive when aldosterone levels are increased. Eplerenone (Inspra) is an Indapamide (Lozol ) 24–36 analog of aldosterone that produces fewer adverse effects. Two other Metolazone (Zaroxolyn) 12–24 drugs, amiloride (Midamor) and triamterene (Dyrenium), reduce aldosteOrganic acids (loop diuretics) rone activity by blocking the sodium channel in the collecting ducts of the Bumetanide (Bumex) 4–6 nephron. These drugs are also more Ethacrynic acid (Edecrin) 6–8 effective when aldosterone levels are increased. Because these diuretFurosemide (Lasix) 6–8 ics increase potassium levels in the blood, they are often referred to as Torsemide (Demadex) 6–8 “potassium-sparing diuretics.” The potassium-sparing diuretics are frePotassium-sparing diuretics quently combined with thiazide and loop diuretics to counterbalance the Amiloride (Midamor) 24 loss of potassium by these diuretics. The adverse effects of the thiaEplerenone (Inspra) 12–24 zides and loop diuretics are similar and include nausea, hypotension, Spironolactone (Aldactone) 48–72 hypokalemia, hyperuricemia, and hyperglycemia. The main adverse Triamterene (Dyrenium) 12 effect associated with the potassium-sparing diuretics is hyperkalework and oxygen consumption. The heart is able to mia. More detailed information on the mechanisms of pump more efficiently (increased cardiac output) with action and adverse effects of the diuretics is discussed less effort. Drugs that primarily dilate arteries have in Chapter 25. a greater effect to lower arterial blood pressure. This effect is referred to as decreasing the afterload of the LO 22.3 heart, which simply stated means that the heart doesn’t VASODILATOR THERAPY OF CHF have to work as hard to pump blood after the blood presThe main effect of vasodilator drugs is to relax or dilate sure has been lowered. Drugs that primarily dilate veins blood vessels. Vasodilation lowers peripheral resistance (venodilators) mainly decrease the venous return of and blood pressure. These changes decrease cardiac blood back to the heart. This is referred to as decreasing Chapter 22 • Treatment of Heart Failure
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preload, which also reduces cardiac work. Some drugs dilate both arteries and veins and produce a “balanced” vasodilation that decreases both pre- and afterload. Vasodilator therapy of CHF has been shown to be very beneficial, especially with the drug classes known as the angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). These drugs have become the preferred agents for the treatment of CHF. There is less risk of toxicity with these vasodilators than with drugs such as digoxin. Vasodilator drugs are used alone and in combination with other drugs. The vasodilators can be divided into different subtypes— arterial dilators, venous dilators, and balanced dilators— based on their sites and mechanisms of action.
Arterial Dilators Hydralazine is a drug that produces arterial vasodilation, decreased blood pressure, and a reduction in afterload. The mechanism of action is believed to involve the formation of nitric oxide (NO), a substance normally produced in the vasculature that produces vasodilation. By reducing systemic blood pressure, the force (afterload) that the left ventricle must generate in order to eject blood is reduced. The result in CHF is an increase in CO. Adverse effects are mostly due to excessive decreases in blood pressure and include nausea, postural hypotension, headache, and reflex tachycardia.
Venodilators Nitrate drugs such as nitroglycerine and isosorbide dinitrate (also discussed in Chapter 24) primarily cause venodilation, especially of the larger veins and vena cava. When the heart is congested and overloaded with blood, the contractile force is greatly reduced. Venodilators reduce venous return and preload. The amount of blood returning to the heart is decreased, which allows the heart to pump more forcefully to increase CO. Adverse effects of the nitrates include headache, dizziness, vasomotor flushing, postural hypotension, and reflex tachycardia.
Balanced Vasodilators These drugs dilate both arteries and veins. Angiotensinconverting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are two rather large classes of drugs that produce this effect. These drugs inhibit the actions of angiotensin II, which causes vasoconstriction, release of aldosterone, and release of ADH. Aldosterone and ADH cause retention of sodium and water. ACEIs have two mechanisms of action. First, they inhibit the angiotensin-converting enzyme (ACE), which reduces the formation of angiotensin II. This action promotes
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vasodilation and excretion of sodium and water from the kidneys. Second, inhibition of ACE also decreases inactivation of bradykinin. Bradykinin is an endogenous vasodilator and this action increases bradykinin levels in the plasma and contributes to the vasodilation produced by the ACEIs. ARBs bind to and block the angiotensin II receptor, referred to as the angiotensin-1 (AT1) receptor. This blocks the actions of angiotensin II and results in vasodilation and increased excretion of sodium and water. ARBs do not affect bradykinin. Figure 22.3 illustrates the sites of action of the ACEIs and ARBs. Both drug classes produce a balanced vasodilatation that reduces both pre- and afterload. These drugs have become the preferred therapy for CHF and can be combined with diuretics and other drugs indicated for CHF. The major difference between the ACEIs and the ARBs is that the ARBs do not increase bradykinin concentrations. While bradykinin contributes to the vasodilation, it also increases adverse respiratory and allergic reactions. Adverse effects of both ACEIs and ARBs include headache, dizziness, hypotension, hyperkalemia, and GI disturbances. The ACEIs also can cause a dry cough and allergic reactions that may include angioedema. The cough and allergic reactions are thought to be related to the increased levels of bradykinin, which can increase the formation of allergic and inflammatory chemical mediators. The vasodilator drugs are summarized in Table 22:2. LO 22.4
USE OF ADRENERGIC BETABLOCKERS IN CHF The pharmacology of beta-blockers was presented in Chapter 6; a brief review of the mechanism of action and adverse effects of these drugs may be helpful. Betablockers bind to beta adrenergic receptors and block the actions of norepinephrine and epinephrine. The therapeutic action of beta-blockers in CHF is to block beta-1 receptors on the heart; this decreases heart rate and force of contraction. These actions would seem to be opposite to the effects required in CHF. However, in CHF, there is excessive activation of the sympathetic nervous system that causes tachycardia and increased stress on the heart. By slowing the heart rate, beta-blockers allow the heart to fill and function more efficiently. There are also beta-1 receptors on specialized cells in the kidneys, the juxtaglomerular cells that release renin. Remember that the renin-angiotensinaldosterone mechanism causes vasoconstriction and
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Sites of Action of the Angiotensin-Converting Enzyme Inhibitors (ACEIs) and Angiotensin Receptor Blockers (ARBs)
Figure 22.3
Angiotensinogen
Kininogen
Renin Angiotensin l
Bradykinin (ACE) Angiotensin-converting enzyme
Vasodilation
1 Angiotensin-converting enzyme inhibitor (ACEI) Angiotensin ll
A II A II
A II
Effect of ACEIs
Inactive metabolite
X X X 2 ARB ARB ARB ARB
Angiotensin-l (AT-1) receptor
Angiotensin-l (AT-1) receptor
Vasoconstriction
Vasodilation
Increased aldosterone
Decreased aldosterone
Increased ADH
Decreased ADH
Increased pre-afterload
Decreased pre-afterload
Effects of both ACEIs and ARBs
(1) ACEIs inhibit the enzyme ACE and decrease the formation of angiotensin II. This produces vasodilation and decreased release of aldosterone and ADH. In addition, by inhibiting ACE, ACEIs increase the concentration of bradykinin and vasodilation. (2) ARBs bind to the angiotensin-1 (AT 1 ) receptor and block angiotensin II from producing its effects. ARBs block the actions of angiotensin II but do not increase bradykinin concentrations.
retention of sodium and water. Therefore, blocking these beta-1 receptors reduces the release of renin and activation of the RAA mechanism. Any of the betablockers will produce the desired therapeutic effects, but metoprolol (Lopressor) and carvedilol (Coreg) are usually the preferred drugs for treatment of CHF. In addition to blocking beta receptors, carvedilol also produces vasodilation by blocking adrenergic alpha-1 receptors. The dosages of beta-blockers in CHF are usually in the lower therapeutic range and it is important not to cause excessive beta blockade of cardiac
function, which would then decrease contractility and cardiac output. LO 22.5
CARDIAC GLYCOSIDES The cardiac glycosides are a group of compounds originally obtained from the plant leaves of Digitalis purpurea and Digitalis lanata. The term digitalis also refers to these drugs. The major action of these drugs is to increase cardiac contractility. Digoxin (Lanoxin) is the
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Table 22:2
Vasodilators Used to Treat Chronic Heart Failure Drug (Trade Name)
Mechanism of action
Therapeutic effect
Increases endothelial release of NO* to produce relaxation of arteriolar smooth muscle
Decreased afterload, increased CO**
Leads to formation of NO, which primarily causes relaxation of venous smooth muscle
Decreased preload, increased CO
Arterial dilators Hydralazine (Apresoline)
Venodilators Isosorbide dinitrate (Isordil ) Nitroglycerine (generic) Balanced vasodilators Angiotensin-converting enzyme (ACE) inhibitors Benazepril (Lotensin) Captopril (Capoten) Enalapril (Vasotec) Fosinopril (Monopril ) Lisinopril (Prinivil, Zestril ) Ramipril (Altace) Trandolapril (Mavik)
ACE inhibitors block the enzymatic conversion of angiotensin I to angiotensin II, decrease the release of aldosterone and ADH. This produces a balanced vasodilation of both arteries and veins and reduces sodium and water retention. ACEIs also increase bradykinin levels which contributes to the vasodilating effect
Decreased pre- and afterload, increased CO, reduction of cardiac remodeling
All ARBs block the binding of angiotensin II to angiotensin receptor sites. The angiotensin receptor is referred to as the AT1 receptor. Effects are similar to the ACE inhibitors, except that ARBs do not increase bradykinin
Decreased pre- and afterload, increased CO, reduction of cardiac remodeling
Angiotensin receptor blockers (ARBs) Candesartan (Atacand) Irbesartan (Avapro) Losartan (Cozaar) Telmisartan (Micardis) Valsartan (Diovan)
*NO-nitric oxide. **CO-cardiac output.
only drug of this class that is still available in the United States, so this discussion will focus on the pharmacology of digoxin.
Pharmacological Effects The unique and main pharmacological effect of digoxin is to increase the force of myocardial contractions (also referred to as a positive inotropic effect) in CHF without causing an increase in oxygen consumption. The efficiency of the heart is improved, restoring normal blood circulation. Kidney function increases due to the increased cardiac output and renal blood flow. This
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increase in kidney function contributes to the elimination of the excess fluid and electrolytes associated with edema. A second action of digoxin is to stimulate the vagus nerve (parasympathetic effect), which slows the activity of the SA and AV nodes. This slows the heart rate (also referred to as a negative chronotropic effect) and decreases AV conduction. On the electrocardiogram (ECG) this is observed as a lengthening of the PR interval. At higher doses, the decreased conduction through the AV node can lead to various degrees of heart block.
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Heart block occurs when conduction of electrical impulses from the atria through the AV node to the ventricles is delayed or blocked. A slight delay in AV conduction is useful in the treatment of atrial flutter and atrial fibrillation. In these conditions, digoxin reduces the ventricular rate by slowing conduction through the AV node. This causes prolongation of the PR interval and is referred to as first-degree heart block. Second-degree heart block is characterized by failure of some impulses to get through the AV node. The result is that every P wave is not followed by a QRS wave. When every other P wave is blocked the arrhythmia is referred to as 2:1 AV block. Other ratios also can be seen, for example, 3:1, 4:1, and so on. In third-degree or complete heart block, no impulses go through the AV node and the atria and ventricles beat independently. Second- and third-degree heart block are arrhythmias that require treatment. ECG tracings of the different degrees of heart block can be seen in Chapter 23, Figure 23.1.
relieve the symptoms of heart failure. Figure 22.4 illustrates the mechanism of action of digoxin.
Pharmacokinetics In acute CHF, the administration of digoxin normally follows a sequence known as digitalization and maintenance. During digitalization, digoxin is administered (PO or IV) at doses and intervals that rapidly produce an effective blood level. Subsequent daily maintenance doses are lower and adjusted to maintain a therapeutic level of glycoside in the blood. Digoxin can be administered orally or intravenously, depending on the urgency of the situation. Food
Figure 22.4 Mechanism of Action of Digoxin Cardiac Muscle Cell
Special Considerations Before administering glycosides, a patient’s pulse should be taken to ensure that the heart rate is between 60 and 100 beats per minute. If the rate is below 60 or above 100, the attending physician should be consulted before the drug is given. In addition, the heart rhythm should be normal.
Extracellular 1
Digoxin inhibits Na/K ATPase
Mechanism of Action Digoxin increases the force of myocardial contractions by increasing the concentration of calcium ions inside cardiac muscle cells. First, digoxin inhibits the enzyme Na/K adenosine triphosphatase (Na/K ATPase), which energizes the sodium/potassium pump. Normally, the sodium/potassium pump removes sodium from inside the cell (depolarization) and brings potassium back into the cell (after repolarization). Inhibition of Na/K ATPase leads to accumulation of sodium ions inside heart muscle cells. Second, the increase of sodium ions inside heart muscle reduces the activity of another ion exchange mechanism, the sodium-calcium (Na/Ca) exchanger. Normally the Na/Ca exchanger brings Na+ into the cell and pumps Ca++ out of the cell. Inhibition of the Na/K ATPase increases the concentration of Na+ inside the cell. The increased intracellular Na+ slows the Na/Ca exchanger and slows the loss of intracellular Ca++. The resulting increased intracellular calcium concentrations increase the formation of the contractile protein actinomyosin, resulting in greater myocardial contraction. After treatment with digoxin, the heart contracts more forcefully to increase cardiac output and
Intracellular
Na/K ATPase
Na a
Na ions increase inside muscle
Na Na Na Na Na Na 3 Increased Na ions decrease the exchange of Ca Na
K Na Na/Ca Exchanger
2
Ca
Ca
Ca
Increased Ca increases formation of actinomyosin
Ca 4
(1) Digoxin binds to and inhibits Na/K ATPase. (2) Inhibition of Na/K ATPase increases intracellular concentration of Na + ions. (3) Increased intracellular Na + decreases the Na +/Ca ++ exchanger and allows intracellular Ca ++ concentrations to increase. (4) Increased intracellular Ca ++ increases the formation of actinomyosin and increases the force of myocardial contractions.
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may delay absorption but usually does not interfere with the extent of absorption. Digoxin is not bound significantly to plasma proteins and is excreted mostly unmetabolized by the urinary tract. The half-life of digoxin is normally 1.5 to 2.0 days, but it may be prolonged in older patients.
The Effects of Serum Electrolyte Levels on Digoxin The actions of digoxin are affected by changes in the serum electrolytes, particularly potassium and calcium. Hypokalemia (low serum potassium) sensitizes the heart to the toxic effects of digoxin. Decrease in serum potassium may cause an increased incidence of arrhythmias, which can lead to ventricular fibrillation and sudden death. Administration of potassium salts is required to restore normal electrolyte levels during these crises. In contrast, hyperkalemia (high serum potassium) antagonizes the therapeutic effects of digoxin. Hypercalcemia (high serum calcium) enhances the action of digoxin and can lead to arrhythmias. Many patients with CHF also are treated with diuretics to reduce the edema associated with this condition. It is important that these patients receive adequate amounts of potassium in their diets to counterbalance the excretion of potassium caused by diuretics. Fruit juices, bananas, and vegetables are good sources of dietary potassium. In addition, there are commercial preparations of potassium supplements such as K-Lyte or Slow-K.
Adverse and Toxic Effects The major adverse effects of digoxin are caused by excessive dosage. Mild symptoms include nausea, vomiting, headache, visual disturbances, and rashes. Dose reduction is usually sufficient to relieve these symptoms. The serious toxic effects involve the development of cardiac arrhythmias. Usually, there is an appearance of extra heartbeats (ectopic beats). Most common are premature ventricular contractions (PVCs). An increase in these contractions can lead to ventricular tachycardia, ventricular fibrillation, and cardiac arrest. Treatment involves stopping digoxin and administering potassium and antiarrhythmic drugs to restore the normal cardiac rhythm. In overdose toxicity, an antidote is available to reduce the severity of toxicity. Digoxin Immune Fab (Digibind) is a preparation of antidigoxin antibodies that is administered parenterally. The antibodies bind up digoxin and make it unavailable for producing its pharmacological effects. The symptoms and severity of toxicity are usually reduced within 30 to 60 minutes. The
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antibody-digoxin complex is eliminated in the urine. The main indication for Digoxin Immune Fab is treatment of life-threatening digoxin intoxication.
Clinical Indications The main use of digoxin is the treatment of CHF, to increase the force of contractions. Digoxin also is used in some cases of atrial flutter and atrial fibrillation. The intent is to produce first-degree heart block and slow AV conduction. This reduces the ventricular rate and prevents the ventricles from excessive stimulation.
Drug Interactions Antacids, laxatives, kaolinpectin (Kaopectate), and cholestyramine (Questran) can decrease the absorption of digoxin from the GI tract. The antiarrhythmic drug quinidine increases digoxin plasma levels. Reduction in digoxin dosage is usually required when these two drugs are used together. The calcium channel blockers verapamil and diltiazem and any of the beta-blockers decrease heart rate and force of contraction. These drugs may depress cardiac function and precipitate CHF; this can counteract the therapeutic effectiveness of digoxin. Diuretics (thiazides and loop diuretics) cause loss of potassium; hypokalemia can increase digoxin toxicity.
Other Drugs That Increase Myocardial Contraction There are several drugs that are administered by IV infusion in the treatment of acute heart failure. Dopamine and dobutamine (Dobutrex) are adrenergic drugs (see Chapter 6) that stimulate beta-1 receptors and increase the force of contraction. Amrinone and milrinone (Primacor) are drugs that increase contractility by increasing calcium concentrations in heart muscle; these drugs also produce vasodilation. The use of these drugs is limited and administered primarily in the hospital setting during the initial treatment of acute heart failure until the patient is stabilized and other therapeutic decisions can be made.
Preferred Therapy for Chronic Heart Failure Chronic heart failure can be caused by a variety of conditions including hypertension, coronary artery disease, and myocardial infarction. Consequently, drug selection for CHF also must consider the drugs required to treat these conditions. In mild CHF, restriction of sodium intake and diuretic therapy may be sufficient to control the edema, congestion, and decreased cardiac output. As CHF becomes more severe, the preferred drugs to
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Patient Administration and Monitoring Monitor vital signs during administration of digoxin, especially during digitalization and parenteral administration. Pay particular attention to heart rate. Monitor the ECG for cardiac arrythmias and signs of digoxin toxicity such as excessive ST segment and T wave depression or heart block. Always measure the pulse rate before administering digoxin. The physician should be notified when the heart rate is below 60 or above 100 beats per minute.
Explain to patient that common over-the-counter drugs such as antacids and laxatives may reduce drug absorption. Explain to patient the common side effects: nausea, headache, dizziness, and visual disturbances. Instruct patient to report excessive vomiting, visual disturbances (halo effect around lights), irregular pulse rates, or heart palpitations.
Instruct patient on the importance of adequate potassium intake and that fruit juices, bananas, and vegetables are good sources.
add are usually the angiotensin-converting enzyme inhibitors (ACEIs) or the angiotensin receptor blockers (ARBs). These drugs produce multiple actions to produce a balanced vasodilation and inhibit the retention of sodium and water. If there is tachycardia and evidence of
increased sympathetic activation, low-dose beta-blocker therapy can be added. Digoxin is considered when diuretic and vasodilator therapy are unable to effectively control symptoms and when myocardial contractility is weak and unable to maintain cardiac output.
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Chapter Review Understanding Terminology Answer the following questions. 1.
Define CHF. (LO 22.1)
2.
What are ectopic beats? (LO 22.5)
3.
Differentiate between hyperkalemia and hypokalemia. (LO 22.5)
Acquiring Knowledge Answer the following questions. 1. What is the main action of digoxin on heart rate and force of myocardial contraction? (LO 22.5) 2. Explain the use of aldosterone antagonists in treatment of CHF. (LO 22.2) 3. Explain the clinical importance of digitalization and tell how digitalization differs from maintenance. (LO 22.5) 4. Compare the pharmacologic effects of the arterial dilators and venodilators. (LO 22.3) 5. What precautions should be observed prior to administration of digoxin? (LO 22.5) 6. Why are beta-blockers useful in CHF? (LO 22.4) 7. What is the mechanism of action of angiotensin receptor blockers? (LO 22.3) 8. What role do thiazide and loop diuretics play in the treatment of congestive heart failure? (LO 22.2) 9. Explain why balanced vasodilator drugs are beneficial in the treatment of congestive heart failure. (LO 22.3)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. Mrs. McNally is a 65-year-old female who presents at the clinic where you’re working with complaints of increased shortness of breath and swelling of her feet. Her past medical history includes a diagnosis of hypertension and moderate degree of renal failure. Pertinent laboratory tests show a slightly decreased potassium level of 3.2 M/l (normal 3.5–5 M/l) and an increased serum creatinine of 2.1 mg/dl (normal 0.8–1.5 mg/dl). The physician’s diagnosis is acute congestive heart failure. The physician’s course of therapy includes doubling Mrs. McNally’s dose of hydrochlorothiazide from 25 mg to 50 mg daily and prescribing digoxin 0.25 mg twice daily for 2 days and then 0.25 mg daily. a. What is the most likely electrolyte disturbance that may occur in this patient? (LO 22.5) b. What does the increased level of serum creatinine suggest about this patient’s renal function? (LO 22.5) 2. Outline the steps to be taken in severe cardiac glycoside intoxication. (LO 22.5) 3. Explain the rationale behind the use of digoxin in the treatment of atrial fibrillation. (LO 22.5)
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Multiple Choice Use your critical-thinking skills to answer the following questions. 1. The therapeutic actions of angiotensin-converting enzyme (ACE) inhibitors include (LO 22.3) A. arterial dilation B. elimination of sodium C. venous dilation D. all statements are true 2. The mechanism of action of triamterene (Dyrenium) is to (LO 22.2) A. block aldosterone receptors B. increase sodium excretion at loop of Henle C. block sodium channels at nephron collecting ducts D. increase the release of aldosterone 3. The actions of digoxin (Lanoxin) include (LO 22.5) A. decreased heart rate B. inhibition of Na/K ATPase C. increased calcium inside heart muscle D. all statements are true 4. The actions of carvedilol (Coreg) include (LO 22.4) A. blockade of beta receptors B. increased force of myocardial contraction C. blockade of alpha-1 receptors D. only A and C are true 5. The most effective drug to relieve edema and congestion in acute heart failure would be (LO 22.2) A. hydralazine (Apresoline) B. furosemide (Lasix) C. metoprolol (Lopressor) D. hydrochlorothiazide (HyroDIURIL)
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Select all of the following that are causes of heart failure. (LO 22.1) A. untreated hypertension B. weakening of contractile force C. myocardial infarction D. valvular defects
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Chapter Review Continued 2. Which medication reduces edema by blocking the reabsorption of sodium in the distal tubules? (LO 22.2) A. eplerenone B. torsemide C. triamterene D. chlorothiazide 3. Vasodilators increase afterload work on which part of the circulatory system? (LO 22.3) A. veins B. arteries C. cardiac nervous tissue D. myocardium 4. Select the adverse effects of digoxin. (LO 22.5) A. atrial tachycardia B. hypokalemia C. ventricular fibrillation D. angioedema 5. The main effects of beta blockers include (LO 22.1, 22.4) A. slowing the heart rate B. reducing the release of renin C. decreasing vasoconstriction D. decreasing sodium retention
Classification Place the following drug effects under the correct type of vasodilator. (LO 22.3) reduce venous return inhibit angiotensin II reduce systemic blood pressure decrease aldosterone reduce preload dilate both veins and arteries increase release of NO leads to formation of NO reduce afterload
Arterial dilators
Venodilators
Balanced dilators
Matching Match the following terms with their correct definition. (LO 22.1, 22.2, 22.3, 22.4, 22.5) a. hyperkalemia b. hypercalcemia c. hypokalemia d. preload
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e. f. g. h.
afterload digitalization cardiac output ectopic beat
1. 2. 3. 4. 5. 6. 7. 8.
_____ _____ _____ _____ _____ _____ _____ _____
method of dosage with digoxin that rapidly produces effective drug levels high serum calcium extra heartbeat measure of vascular resistance high serum potassium amount of venous return low serum potassium amount of blood pumped per minute
Documentation Using the prescription below, answer the following questions. (LO 22.2)
Riverview Cardiology Practice RX 12345 Main Avenue Anytown, USA 12345 931-555-1000 NAME:
Kathy Hart
DATE:
ADDRESS: RX
hydrochlorothiazide 25mg
Sig:
Take one tablet by mouth once daily
Dr. Craig River Substitution Permitted DEA #:
a. b. c. d.
M.D.
M.D. Dispense as written REFILL:
NR
1
2
3
4
What symptom of CHF is being treated with this drug? What condition can this medication cause? What is the duration of action of this medication? Is this medication the best choice for someone with renal impairment? If not, what class of diuretics would be?
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Chapter Review Continued Labeling Fill in the missing labels. (LO 22.1)
Liver
Kidney
Angiotensinconverting enzyme (ACE)
Lungs
Hypothalamus
Cardiovascular system
ADH
Adrenal cortex
Kidney
For interactive animations, videos, and assessment, visit:
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Chapter 23
Antiarrhythmic Drugs DRUG CLASS AT A GLANCE
KEY TERMS
OTC
antiarrhythmic drug: drug used to restore normal cardiac rhythm.
NO
PRESCRIPTION YES SCHEDULED DRUGS
NO
FDA P REGNANCY CATEGORY
B, C, D—Amiodarone, verapamil
INDICATIONS Cardiac arrhythmias
arrhythmia: disorder of cardiac conduction and electrical impulse formation. cinchonism: quinidine toxicity, which is characterized by ringing in the ears (tinnitus), dizziness, and headache. ectopic focus: area of the heart from which abnormal impulses originate. premature atrial contraction (PAC): premature contraction of the atria, usually caused by an ectopic focus. premature ventricular contraction (PVC): premature contraction of the ventricles, usually caused by an ectopic focus. proarrhythmia: an arrhythmia caused by administration of an antiarrhythmic drug. supraventricular arrhythmia: arrhythmia that originates above the AV node in the atria. torsade de pointes: a type of proarrhythmia that causes ventricular tachycardia and fainting. ventricular fibrillation: the most serious arrhythmia; usually a terminal event where ventricular contractions are no longer able to effectively pump blood.
Learning Outcomes
After studying this chapter, you should be able to 23.1 identify the basic terminology and descriptions associated with cardiac arrhythmias. 23.2 describe the phases of the cardiac action potential in relationship to the activity of Na, K, and Ca ions.
23.3 explain the mechanism of action and main differences between the IA, IB, and IC antiarrhythmic drugs. 23.4 describe the antiarrhythmic actions and uses of the beta-blockers. 23.5 explain the mechanism of action of the class III antiarrhythmic drugs and describe the most serious adverse effects of amiodarone.
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23.6 describe the antiarrhythmic actions of the calcium channel blockers and their clinical uses.
23.7 recognize the special precautions required with the use of antiarrhythmic drugs.
Introduction
An arrhythmia is any abnormality in heart rate or rhythm of electrical conduction through the heart. Arrhythmias disturb the electrical activity of the heart and interrupt the normal sequence of atrial and ventricular activation and contraction. The physiologic consequences of arrhythmias are usually a decrease in cardiac output and blood pressure. In addition, the electrical disturbances can lead to life-threatening arrhythmias such as ventricular fibrillation and cardiac arrest. The type of arrhythmia depends on the location in the heart and the severity of the electrical disturbance. The causes of arrhythmias are numerous and include ischemic conditions such as coronary artery disease (CAD), electrolyte disturbances (Na, K, Ca) caused by diuretics and drug toxicities, myocardial infarction, and other pathological conditions. Arrhythmias are identified and classified by evaluation of the electrocardiogram (ECG). The clinical management of arrhythmias involves the use of antiarrhythmic drugs that primarily affect the activity of sodium (Na), potassium (K), and calcium (Ca) ions. These ions normally regulate the electrical activity of the heart. The therapeutic aim of antiarrhythmic drugs is to modify the activity of these ions so that normal heart rhythm is restored.
LO 23.1 1
LO 23.2
TYPES OF ARRHYTHMIAS Arrhythmias are often caused by electrolyte disturbances and overstimulation of the heart. Arrhythmias can originate anywhere in the heart, in the atria, ventricles, or conduction system. The most common types of arrhythmias include tachycardias, premature contractions, flutters, and fibrillations. Electrocardiogram recordings of various cardiac arrhythmias are illustrated in Figure 23.1. Arrhythmias that originate in the atria and atrioventricular (AV) nodal areas are referred to as supraventricular arrhythmias (above the ventricles). Paroxysmal atrial tachycardia, atrial flutter, and atrial fibrillation are common supraventricular arrhythmias. Paroxysmal atrial tachycardia is characterized by atrial rates of 150 to 200 beats per minute. This arrhythmia is unpredictable and can suddenly develop; it also can spontaneously terminate. The individual may experience anxiety, heart palpitations, and symptoms of heart failure if the arrhythmia persists. In atrial flutter the atrial
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rate is between 250 and 350 beats per minute. Instead of normal P waves, the ECG shows smaller waves with a sawtooth-like pattern. The ventricles cannot keep up with the atria and contract at a slower rate. In atrial fibrillation the atrial rate is over 350 beats per minute and the ventricular rhythm is irregular. On the ECG the atrial waves are described as a “bag of worms” and there are no effective atrial contractions. This predisposes the atria to the development of blood clots (thromboembolism). Arrhythmias that originate below the AV node are referred to as ventricular arrhythmias. Ectopic foci, areas of abnormal impulse generation, may appear when electrical impulses traveling through the conduction system are delayed or blocked. In this situation, another area of the heart (atrium or ventricle) may become excitable and produce an abnormal heartbeat. Ectopic foci that originate in the atria are referred to as premature atrial contractions (PACs). A PAC would be classified as a supraventricular arrhythmia. Ectopic foci that originate in the ventricles are referred to as premature ventricular contractions (PVCs). Figure 23.2
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Figure 23.1
Electrocardiographic Recordings of Common Cardiac Arrhythmias P
Normal sinus rhythm
P
P
Premature atrial beat
Premature atrial beat Additional beat has normal waveform
P
P
P
Paroxyamal atrial tachycardia P
Run of rapid beats with each QRS complex preceded by a P wave
P P P P
Atrial fibrillation No defined P waves present. Random triggering of QRS complexes, which are normal in shape P
First-degree heart block
P
P
Abnormally long PR intervals
PR
Type I second-degree heart block Skipped ventricular beat. Example of type I second-degree (Wenckebach) block in which PR interval lengthens progressively, until a beat is missed
Type II second-degree heart block Dropped ventricular beat, which is not preceded by PR interval lengthening
P
P
P
PR
PR QRS
Premature ventricular contraction QRS complex occurs without a P wave and has an abnormal shape
P
P
P
No QRS
P
PR
PR
Third-degree heart block P waves are dissociated from QRS complex
P
P
P
No QRS
PR QRS
P
PVC
P P
P
P
QRS P
P
P
P
Ventricular fibrillation No defined ECG waves
shows the appearance of a PVC produced by a ventricular ectopic focus. In this arrhythmia the PVC depolarizes the ventricle before the SA node and atrium. The electrical impulse travels up the conduction system (instead of down) toward the atrium. The result is a QRS wave that is inverted and that disrupts normal ventricular contraction. Ventricular tachycardia is a rapid ventricular
rhythm where three or more PVCs occur consecutively. Ventricular tachycardia can cause significant circulatory impairment and may lead to ventricular fibrillation. The most serious arrhythmia is ventricular fibrillation, which constitutes a medical emergency. During fibrillation, the electrical activity of the ventricles is severely disturbed and the ventricles cannot
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potential. During Phase 0 influx of Na+ ions depolarizes the cardiac membrane and generates an action potential. During Phases 1–3 the membrane is undergoing repolarization as K+ ions efflux out of the cardiac membrane. During Phase 2 (plateau) calcium channels open and Ca++ ions pass into the muscle cell and function in myocardial R contraction. In Phase 4 the membrane PVC PV VC C potential has returned to its resting level and is ready for the next action P Q potential. In the SA and AV nodes, the S slope of Phase 4 increases upward and functions to automatically generate an action potential. This property is referred to as automaticity. Ventricular muscle does not normally display Ectopic focus automaticity. However, it can develop automaticity when there is ischemia, excessive sympathetic stimulation, or The ectopic focus depolarizes the ventricle before the SA node and other abnormal conditions. When this atrium. The electrical impulse travels up the conduction system and the occurs ventricular muscle can depolarQRS wave is inverted and abnormal in appearance. ize and generate a premature ventricular contraction (PVC). The heart possesses several important electrocontract efficiently enough to maintain adequate circulaphysiologic properties, including conduction, refraction. If not treated immediately, cardiac arrest and death toriness, and automaticity. Table 23:1 describes these will result. properties and correlates them with the phases (0–4) ECG Monitoring of Arrhythmias of the ventricular action potential ( Figures 23.3 and The characteristic pattern of an electrocardiogram 23.4). An ECG recording is an electrical summation (ECG) was reviewed in Chapter 21, Figure 21.3. Elecof all the individual cardiac action potentials. On the trocardiograms are extremely valuable for determining ECG, Phase 0 corresponds to the ventricular QRS abnormalities in cardiac rhythm and conduction. Heart wave. The time required for Phases 0–4 represents the rate can be determined by counting the number of QRS QT interval. waves that occur within a 1-minute period. AbnormaliAntiarrhythmic drugs that slow Phase 0, prolong ties in the appearance of the ECG waves and measurePhases 1–3, or decrease Phase 4 automaticity produce ments of the ECG intervals (PR, QRS, QT) that are not effective antiarrhythmic actions. Most antiarrhythmic within normal limits indicate abnormalities of conducdrugs affect the movement of one or more specific ions tion. The duration of the PR interval reflects the time and exert their major antiarrhythmic action on a specific required for conduction from the SA to the AV node, phase of the action potential. the duration of the QRS wave reflects the time for When some part of the heart develops an arrhythdepolarization and conduction through the ventricles, mia, the properties of the heart and the movement of and the QT interval reflects the time for depolarization the ions are disturbed. The therapeutic effects of antiand repolarization of the ventricles. arrhythmic drugs rest in their ability to affect the electrophysiological properties of the cardiac membrane Electrophysiology of the Heart and the movement of ions so that the properties of the One of the most important aspects of the heart is the heart are restored to normal or are at least improved. function of several ions that regulate the electrophysiOne cautionary note should be mentioned: all antiarological properties of the heart. The ions are sodium rhythmic drugs have the potential to make any exist(Na+), potassium (K+), and calcium (Ca2+). Each ion ing arrhythmia worse. In addition, antiarrhythmic has a specific role in generation of the cardiac action drugs can cause new arrhythmias. A new or different Figure 23.2
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Illustration of a Ventricular Ectopic Focus or Premature Ventricular Contraction (PVC)
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Phases of the Cardiac Action Potential of Ventricular Muscle
Figure 23.3
+30 mV
1 Ca⫹⫹ 2
0 mV
Depolarization
0
Repolarization 3
Na⫹
K⫹
Automaticity
4 290 mV During Phase 0, sodium ions influx into the muscle cell and depolarize the membrane. This generates an action potential that is conducted along the membrane and throughout the ventricles. During Phases 1–3, potassium ions pass out of the muscle cell and the membrane is repolarized. During Phase 2, calcium channels open and calcium ions pass into the muscle and are involved in muscle contraction. Phase 4 reflects the property of automaticity, which is normally absent in ventricular muscle; however, ischemia and excessive sympathetic stimulation can increase ventricular automaticity (dashed line) and cause premature ventricular contractions (PVCs).
arrhythmia caused by administration of an antiarrhythmic drug is referred to as a proarrhythmia. One of the most common proarrhythmias is referred to as torsade de pointes. This arrhythmia occurs with drugs that cause excessive prolongation of the QT interval, which can lead to hypotension, fainting, and ventricular arrhythmias. Antiarrhythmic drugs are usually classified according to the Vaughn-Williams classification system, which organizes the antiarrhythmic drugs into four major classes based on their major mechanism of action. These drug classes and their main pharmacologic features are summarized in Table 23:2. LO 23.3
CLASS 1 ANTIARRHYTHMIC DRUGS: SODIUM CHANNEL BLOCKERS One of the common features of the Class 1 antiarrhythmic drugs is that they possess local anesthetic activity. Like local anesthetics, the Class 1 drugs block the influx of Na ions during depolarization of nerves and excitable membranes like those of the heart. The primary effect of Class 1 antiarrhythmic drugs is to slow
depolarization and conduction during Phase 0 of the action potential. Class IA antiarrhythmics also slow the efflux of K ions during repolarization, which prolongs the refractory period. These actions suppress arrhythmias in cardiac cells that are hyperexcitable and arrhythmogenic (giving rise to arrhythmias). The Class I drugs are subdivided into three groups (IA, IB, IC) based on the degree to which they block Na ions during depolarization (Phase 0). IAs produce a moderate block; IBs, a mild block; and ICs, a marked block of Na influx (Phase 0). Each Class I drug also produces a different effect on the refractory period (Figure 23.4).
Quinidine (IA)
Chemically related to quinine, quinidine is a natural product obtained from the bark of the cinchona tree. The use of quinidine for cardiac disorders dates back to the eighteenth century, when patients suffering from malaria were treated with extracts of the cinchona bark. The presence of quinidine in these concoctions resulted in improvement in patients in which malaria and atrial flutter occurred simultaneously. In the past quinidine has been used to treat supraventricular arrhythmias, such as atrial flutter and fibrillation, and also ventricular arrhythmias. However, quinidine is a cardiac depressant that decreases myocardial contraction. In addition, quinidine produces anticholinergic and alphablocking effects. Consequently, quinidine can cause a wide range of adverse effects and potential toxicities and is rarely used. The adverse effects of quinidine include nausea, vomiting, and diarrhea due to irritation of the GI tract. Cinchonism is an adverse syndrome produced by quinidine in overdosage or in patients who are sensitive to the drug. This condition is characterized by ringing in the ears (tinnitus), dizziness, salivation, headache, and hallucinations. Quinidine also depresses smooth and skeletal muscle function. Depression of arteriolar smooth muscle may cause hypotension. Depression of skeletal muscle results in weakness and fatigue, which may interfere with respiration (dyspnea). Evidence of quinidine’s electrophysiologic effects can be observed on the ECG. The durations of the PR, QRS, and QT intervals are all increased as a result of the slowed conduction and prolongation of the refractory Chapter 23 • Antiarrhythmic Drugs
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period. These changes may cause premature contractions of the atria and ventricles or proarrhythmias like torsade de points. Less frequently there may be hypersensitivity reactions involving the development of hepatitis and thrombocytopenia. The latter condition can lead to bleeding problems.
+30 mV
1 2
0 mV
Procainamide (Procanbid) (IA) A synthetic drug related to procaine (a local anesthetic), procainamide produces similar antiarrhythmic actions as quinidine. However, procainamide produces less anticholinergic and alpha-blocking actions than quinidine. Procainamide causes fewer adverse effects and toxicities and is the most frequently used IA antiarrhythmic drug. Procainamide may be administered orally or parenterally; however, rapid IV administration may cause a sudden drop in blood pressure. Procainamide has a short half-life and is administered in extended-release tablets (Procanbid ) that allow a 12-hour dosing interval. The drug forms an active metabolite, N-acetylprocainamide (NAPA), that also contributes to the therapeutic effect. Procainamide is effective for both supraventricular and ventricular arrhythmias. However, it is primarily indicated for outpatient treatment of ventricular arrhythmias. Common adverse effects of procainamide include nausea, diarrhea, anorexia, and skin rash. Following chronic use of procainamide, a large percentage of patients develop an antibody referred to as antinuclear antibody. Approximately 20–30 percent of these patients develop a rash and arthralgia similar to the symptoms seen in lupus erythematosus. The development of these symptoms requires that procainamide be discontinued. Procainamide is also capable of producing changes
Illustration of the Different Effects of Class I Antiarrhythmic Drugs on the Cardiac Action Potential
Figure 23.4
0 3
4
290 mV (a)
+30 mV
1 2
0 mV
0 3
4
290 mV (b)
+30 mV
1 2
0 mV
0 (a) Class IA antiarrhythmic drugs produce a moderate decrease in conduction (Phase 0) and prolong the refractory period (Phases 1–3) (dashed line). (b) Class IB drugs produce a mild decrease in conduction and shorten the refractory period. (c) Class IC drugs produce a marked decrease in conduction but do not prolong the refractory period.
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3
290 mV
4
(c)
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Table 23:1
Correlation of Electrophysiological Properties of the Heart with the Phases of the Cardiac Action Potential and the Movement of lons Property
Phase
Ionic movement
Conduction
0
Na+ rapidly moves to the inside of the cell, causing reversal of the membrane potential (–90 mV to +30 mV, and depolarization)
Refractory period (RP)
1–3
K+ moves to the outside of the cell, bringing the membrane potential back (repolarization) to its resting level (–90 mV)
Plateau phase
2
Ca2+ moves to the inside of the cell and is involved in regulating the force of muscle contraction
Automaticity
4
A latent property of ventricular muscle; in pacemaker cells (SA and AV nodes), there is a slow inward movement of Na+ and Ca2+ and an outward movement of K+, which “automatically” excites the membrane and begins another membrane depolarization (Phase 0)
Table 23:2
Vaughn-Williams Classification of Antiarrhythmic Drugs Class
Mechanism of action
Main effects
Drug examples
IA
Moderate block of sodium (Na) channels
Moderate decrease in Phase 0 depolarization; QRS and QT intervals prolonged
Quinidine, procainamide, disopyramide
IB
Mild block of sodium (Na) channels
Mild decrease in Phase 0 depolarization, decrease in ventricular automaticity
Lidocaine, mexiletine
IC
Marked block of sodium (Na) channels
Marked decrease in Phase 0 depolarization, prolongation of QRS interval
Flecainide, propafenone
II
Blockade of adrenergic beta-1 receptors
Decrease in heart rate, AV conduction, and ventricular automaticity; increased PR interval
Propranolol, acebutolol, esmolol
III
Blockade of potassium (K) channels
Prolongation of ventricular repolarization (Phases 1–3), prolongation of QT interval
Amiodarone, dofetilide, ibutilide, sotalol
IV
Blockade of calcium (Ca) channels in SA and AV nodes
Decrease in heart rate and AV conduction, increase in PR interval
Diltiazem, verapamil
in ECGs similar to those produced by quinidine. Usually, increased duration of the PR, QRS, and QT waves occurs. Excessive dosage can cause the development of premature contractions and proarrhythmias. At higher
doses procainamide is also a cardiac depressant. A less frequent adverse reaction is agranulocytosis (decrease in granulocytic white blood cells), which can increase the incidence of infection.
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Note to the Health Care Professional When combined with procainamide or quinidine for the treatment of arrhythmias, lidocaine may produce SA nodal arrest.
Disopyramide (Norpace) (IA) The actions of disopyramide (Norpace) on the heart are similar to those of quinidine and procainamide. Disopyramide produces a decrease in conduction and prolongation of the refractory period. This drug is only approved for treating ventricular arrhythmias. Like quinidine, disopyramide depresses myocardial contractility and is considered a second-line drug with limited clinical usage. In addition, disopyramide produces significant anticholinergic effects that account for the common side effects such as dry mouth, visual disturbances, constipation, and urinary retention. At higher doses or with the development of toxicity, the cardiac depressant effects can cause heart failure.
Lidocaine (Xylocaine) (IB) A synthetic drug used primarily as a local anesthetic agent, lidocaine (Xylocaine) is widely used for ventricular arrhythmias, especially those resulting from a myocardial infarction or arrhythmias occurring during surgery. As a rule, lidocaine is ineffective in atrial arrhythmias and is therefore not recommended for use in these conditions. Although lidocaine suppresses ectopic foci associated with ventricular arrhythmias, it does not depress normal impulse conduction. The main effect of lidocaine, prevention of ventricular arrhythmias, is attributed to its ability to depress automaticity (Phase 4). The major disadvantage of lidocaine is that it must be administered parenterally (IV or IM). Since a single administration results in a very short antiarrhythmic response, lidocaine is usually given as an intravenous infusion to maintain the antiarrhythmic action. Usually, a bolus injection of lidocaine (50 to 100 mg) is initially administered over a 2-minute period, followed by continuous infusion at a rate of 1 to 4 mg per minute. Since lidocaine is rapidly metabolized in the liver, impaired liver function will result in elevated blood levels of lidocaine. At higher concentrations, lidocaine produces a mixed picture of CNS stimulation (tremors, restlessness, convulsions) and CNS depression
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(confusion, slurred speech, paresthesias). Toxic blood levels of lidocaine usually produce CNS depression (anesthetic effect), and possible cardiac and respiratory arrest.
Mexiletine (Mexitil ) (IB) Mexiletine is a derivative of lidocaine that has been structurally modified so that it can be administered orally. Mexiletine produces cardiac effects similar to lidocaine and is used for treatment of outpatient ventricular arrhythmias. Adverse effects are similar to those of lidocaine: lightheadedness, tremors, and other CNS disturbances.
Class 1C Antiarrhythmic Drugs Flecainide (Tambocor) and propafenone (Rythmol) are drugs that are usually reserved for treatment of arrhythmias that are unresponsive to other antiarrhythmic drugs. These drugs markedly depress cardiac conduction (Phase 0). Drug trials with the ICs have shown that these drugs can increase the risk of mortality in patients with preexisting arrhythmias and other cardiac conditions. The IC drugs also depress myocardial contractility and may cause heart failure. Flecainide and propafenone are primarily indicated for treatment of supraventricular arrhythmias. Adverse effects include GI disturbances, bradycardia, heart block, and the potential for heart failure. LO 23.4
CLASS 2 ANTIARRHYTHMIC DRUGS: BETA-BLOCKERS The beta-adrenergic blockers are classified as Class 2 antiarrhythmic drugs. Frequently, in heart disease, there is increased sympathetic activity with increased release of norepinephrine and epinephrine. These adrenergic neurotransmitters increase heart rate, excitability, conduction, and automaticity, particularly of ventricular muscle. In addition, they shorten the refractory period, all of which can contribute to the development of various arrhythmias. By antagonizing the effects of norepinephrine and epinephrine at the beta-1 receptors, beta-blockers decrease heart rate, AV conduction, and automaticity of the SA and AV nodes, and of atrial and ventricular muscle. Beta-blockers are mainly indicated for supraventricular arrhythmias and for prevention of recurrent myocardial infarction. Propranolol, acebutolol, and esmolol are the beta-blockers most frequently used to treat cardiac arrhythmias. The beta-blockers were previously discussed in Chapter 6.
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Note to the Health Care Professional There are two situations in which propranolol and other nonselective beta-blocker administration requires extreme caution. First, propranolol may worsen existing heart failure. Second, because it may produce bronchoconstriction, propranolol will cause respiratory distress in patients with asthma or emphysema.
Propranolol (Inderal ) Propranolol is widely used as an antiarrhythmic drug. In addition to its beta-blocking effect, propranolol produces a depressant effect on cardiac membranes that slows conduction and prolongs repolarization. Propranolol can be administered orally and intravenously in emergency situations. The most common cardiovascular adverse effects are hypotension and bradycardia. In overdosage, propranolol, and other beta-blockers, may cause heart failure and possible cardiac arrest. Skin rashes, mental confusion, and visual disturbances also may occur.
Esmolol (Brevibloc) Esmolol is a selective beta-blocker that mainly affects beta-1 receptors in the heart. It is administered by intravenous infusion in emergency situations when rapid betablockade is desired to lower heart rate. The duration of action is very short, only a few minutes, because of rapid metabolism by esterase enzymes in the blood and liver. Excessive bradycardia, delayed AV conduction, and hypotension are adverse effects associated with overdosage. LO 23.5
CLASS 3 ANTIARRHYTHMIC DRUGS: POTASSIUM CHANNEL BLOCKERS The main antiarrhythmic action of the Class 3 drugs is to block potassium channels and interfere with the efflux of potassium ions (K+) during repolarization Phases 1 through 3. This action prolongs the refractory period of the heart and decreases the frequency of arrhythmias. Amiodarone is the most important drug in this class and has become one of the most frequently prescribed antiarrhythmic drug.
Amiodarone (Cordarone) Amiodarone is a very potent antiarrhythmic drug that has multiple sites of action. In addition to blocking potassium channels, amiodarone blocks sodium (Class 1) and calcium (Class 4) channels. It also has blocking actions on both beta- (Class 2) and alpha-adrenergic receptors. The result is a drug that can be used for most supraventricular and ventricular arrhythmias. When administered IV, the alpha-blocking effect can produce vasodilation and hypotension. The major antiarrhythmic effect is prolongation of the refractory period. On the ECG this is observed by an increase in the duration of the QT interval. The other actions of amiodarone decrease both heart rate and AV conduction; consequently the PR and QRS intervals also are prolonged. Amiodarone is structurally similar to the thyroid hormone thyroxine, contains iodine, and can interfere with thyroid function. The pharmacokinetics of amiodarone are complex. Amiodarone can be administered both orally and intravenously. Oral absorption is incomplete and variable. Drug metabolism produces an active metabolite, desethylamiodarone. The half-life of amiodarone is long and also variable, ranging from 1 to 3 months. Dosages must be carefully regulated and periodic monitoring of serum drug levels is advised. Amiodarone causes numerous adverse effects and potentially serious toxicities. CNS effects include dizziness, tremors, and ataxia. Disturbances of thyroid function, either hypo- or hyperthyroidism, are possible. Pulmonary fibrosis is one of the more serious problems that can occur and can be fatal. Cardiac toxicities include bradycardia, heart block, heart failure, and generation of proarrhythmias such as torsade de pointes. Other adverse effects include a blue-gray skin discoloration, corneal microdeposits, and GI disturbances. Amiodarone is designated Food and Drug Administration (FDA) Pregnancy Category D and should not be used in pregnancy or in nursing mothers.
Sotalol (Betapace) Sotalol is a nonselective beta-blocker that also has Class 3 antiarrhythmic activity. The main effects are prolongation of the refractory period, slowed AV conduction, and decreased automaticity of the heart. Sotalol is primarily indicated for treatment of ventricular arrhythmias and atrial fibrillation. Adverse effects are similar to those of beta-blockers. The major concern with sotalol is its ability to cause torsade de pointes that leads to ventricular tachycardia and fainting.
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Dofetilide (Tikosyn) and Ibutilide (Corvert) Dofetilide and ibutilide are two Class 3 drugs whose actions are limited to blocking potassium channels. Dofetilide is administered orally; ibutilide is administered intravenously. Dofetilide is indicated for the treatment of atrial fibrillation; ibutilide is indicated for the conversion of atrial flutter and atrial fibrillation to normal sinus rhythm. Like other Class 3 drugs, excessive prolongation of the QT interval may cause proarrhythmias such as torsade de pointes. LO 23.6
CLASS 4 ANTIARRHYTHMIC DRUGS: CALCIUM CHANNEL BLOCKERS
Patient Administration and Monitoring Monitor vital signs and ECG recordings frequently during parenteral administration and in newly admitted hospital patients who are still stabilizing and adjusting to therapy. Explain to patient the common side effects of prescribed drugs: Amiodarone—dizziness, tremors, ataxia, GI disturbances Quinidine and procainamide—GI disturbances, headache, dizziness Disopyramide—dry mouth, other anticholinergic effects Propranolol—tiredness, fatigue, GI disturbances, sedation
The Class 4 antiarrhythmic drugs are referred to as the calcium channel blockers. These drugs decrease the entry of calcium into cells whose electrophysiologic actions depend on the influx of calcium through the slow-type calcium channels. In the heart, the depolarization of SA and AV nodal cells is highly dependent on the influx of calcium ions. The effect of calcium channel blockers on the SA node is to slow depolarization and decrease the heart rate. The effect on the AV node is to slow conduction. These actions reduce the ventricular rate during fast supraventricular arrhythmias. The calcium channel blockers also affect the contraction of cardiac and smooth muscle. As indicated in Table 23:1, entry of calcium during Phase 2 of the action potential is important for regulating the force of myocardial contractions. Interference with calcium entry into cardiac muscle reduces myocardial contractility. This is usually not a desired therapeutic action and may precipitate heart failure in patients with CHF. The calcium channel blockers also relax smooth muscle and cause vasodilation, which is useful in the treatment of angina pectoris and hypertension. While all calcium channel blockers produce vasodilation, only verapamil (Calan) and diltiazem (Cardizem) have direct actions on the heart and are used for their antiarrhythmic actions.
rapid AV nodal arrhythmias and other supraventricular tachycardias. Verapamil is administered PO (40 to 120 mg TID) and IV (5 to 10 mg) in emergency situations. Verapamil also produces vasodilation and is used in the treatment of angina pectoris and hypertension (see Chapters 24 and 26). Common adverse effects of verapamil include headache, dizziness, and minor GI disturbances, especially constipation. The vasodilating effect can produce hypotension, especially when patients change position. More serious complications include cardiac depression leading to heart failure and various degrees of heart block, especially if verapamil is taken with other cardiac depressant drugs such as the beta-blockers. Verapamil is usually contraindicated in patients with existing SA and AV node disturbances or with heart failure.
Verapamil (Calan)
Diltiazem (Cardizem)
The major effect of verapamil is on the SA and AV nodes of the heart. Verapamil decreases SA node activity, resulting in a slight decrease in heart rate. More important, verapamil decreases AV node conduction. This effect makes it very useful in treating various types of
The pharmacologic actions, uses, and adverse effects of diltiazem are similar to verapamil. The cardiac depressant effects of diltiazem are slightly less than those of verapamil, but diltiazem is generally considered to be a more potent vasodilator than verapamil.
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Verapamil—headache, dizziness, constipation Instruct patient to report significant changes or adverse effects, especially related to pulse rate, blood pressure, or breathing; with quinidine the signs of cinchonism; with procainamide the development of rash, arthralgia, or infection; with propranolol extreme weakness, slow pulse, or breathing difficulties.
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Adenosine (Adenocard ) Adenosine is considered a miscellaneous antiarrhythmic drug that is only used in emergency and acute situations. Adenosine is the naturally occurring metabolite of adenosine triphosphate (ATP). The drug is administered intravenously to terminate episodes of paroxysmal supraventricular tachycardia. The main effect of adenosine is to decrease the activity of calcium ions in the SA and AV nodes. This causes a slowing of the heart rate and AV conduction, which usually terminates the episode of tachycardia. The duration of action of adenosine is extremely short, 15 to 30 seconds, and may require repeated administrations. Adverse effects are brief, but include asystole, respiratory difficulties (bronchospasm), and hypotension.
drugs carries the risk of causing additional arrhythmias (proarrhythmias) and other serious adverse reactions. The selection of drug therapy is dependent upon the cause of the arrhythmia if it can be determined and other cardiovascular conditions that the patient may be experiencing.
Treatment of Sinus Bradycardia Sinus bradycardia is defined as a heart rate below 60 beats per minute. The most effective drug for this condition is the anticholinergic drug atropine. Atropine increases heart rate and AV conduction, and also contributes to an increase in blood pressure. Nonpharmacologic therapy involves the use of cardiac pacemakers.
Treatment of Atrial Flutter and Atrial Fibrillation LO 23.7
SPECIAL CONSIDERATIONS AND PREFERRED THERAPY FOR SELECTED ARRHYTHMIAS The control of arrhythmias can be a difficult task and patients are often in a precarious situation. Sudden changes in ECGs and the development of life-threatening arrhythmias, like ventricular fibrillation, are always a possibility. In the hospital, ECGs constantly monitor heart patients. It is important to be aware of ECG monitors, to check them frequently, and to be alert for sudden changes in the appearance of ECGs or the condition of patients. Antiarrhythmic drugs are frequently administered in the hospital by IV infusion. Dosages (drips per minute) are carefully adjusted to deliver the proper amount of drug. Other medications frequently are administered through the same IV line; and procedures, like measuring the central venous pressure (CVP), require turning off or adjusting the infusion. It is extremely important that when these other procedures are completed, the infusion rate of the antiarrhythmic drug is adjusted back to its proper rate of delivery. Failure to do this can result in serious consequences for patients. It is important to be aware of the adverse effects of the various antiarrhythmic drugs and to be alert for their appearance. Many of the antiarrhythmic drugs are cardiac depressants and can produce heart failure or any variety of cardiac arrhythmias themselves.
Preferred Therapy for Selected Cardiac Arrhythmias Cardiac arrhythmias are complex and involve a variety of electrophysiologic disturbances. Use of antiarrhythmic
The atrial rate in atrial flutter is between 250 and 350 beats per minute and there is usually a regular ventricular rhythm. The atrial rate in atrial fibrillation is over 350 beats per minute and the ventricular rhythm is irregular. The ventricles are being overstimulated by these two conditions and slowing of the ventricular rate is usually the first consideration. Beta-blockers, calcium channel blockers, and digoxin, which slow AV conduction, are the preferred drugs to stabilize and protect the ventricles. The second concern is to prevent formation of blood clots in the atria (thromboembolism), which involves the use of anticoagulants. The third approach is to terminate the arrhythmia, often with electrical cardioversion. Pharmacologic drugs of choice for chronic treatment to control the ventricular rate are usually beta-blockers, calcium channel blockers, and digoxin.
Treatment of Paroxysmal Supraventricular Tachycardia This arrhythmia involves the sudden onset and termination of supraventricular tachycardia that most commonly involves the AV node. In the acute setting, adenosine (Adenocard ) is the preferred drug. It provides the fastest onset and shortest duration of action. Electrical cardioversion and vagal maneuvers are alternate therapies in acute situations. For chronic therapy of this arrhythmia, there are several choices depending on the patient and other existing conditions. Drugs that slow AV conduction, beta-blockers, calcium channel blockers (verapamil or diltiazem), and digoxin are the preferred drugs.
Treatment of Supraventricular Tachycardia This arrhythmia usually originates in the SA node and causes sustained increases in heart rate over 100 beats per minute. If there is increased sympathetic tone, Chapter 23 • Antiarrhythmic Drugs
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beta-blockers such as propranolol (Inderal ) or metoprolol (Lopressor) are generally preferred. The calcium channel blockers verapamil (Calan) and diltiazem (Cardizem) are also very effective and may be preferred depending on the patient and clinical situation.
Treatment of Ventricular Arrhythmias Premature ventricular contractions (PVC) are the most common type of ventricular arrhythmia. PVCs are also the major cause of ventricular tachycardia.
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Ventricular tachycardia is defined as three or more consecutive PVCs. Since this is a serious condition that can lead to ventricular fibrillation, immediate treatment is required. In the acute setting, the preferred drug is IV administration of amiodarone (Cordarone); IV administration of lidocaine (Xylocaine) is an alternate choice. For the chronic control of ventricular arrhythmias and ventricular tachycardia, amiodarone is usually the preferred drug. Sotalol (Betapace) and beta-blockers are alternate choices.
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Chapter Review Understanding Terminology Match the definition or description in the left column with the appropriate term in the right column. (LO 23.1) ___ 1.
Arrhythmia that originates below the AV node.
a. antiarrhythmic
___ 2.
A drug used to restore normal cardiac rhythm.
b. arrhythmia
___ 3.
Heart area of abnormal electrical impulse generation.
c. ectopic foci
___ 4.
Premature ventricular contraction.
d. ventricular arrhythmia
___ 5.
The most serious type of arrhythmia.
e. PVC
___ 6.
Arrhythmia that originates in the atrial or AV nodal area.
f. supraventricular arrhythmia
___ 7.
A disorder of cardiac conduction.
g. ventricular fibrillation
Acquiring Knowledge Answer the following questions. 1. When would the use of an antiarrhythmic drug be indicated? (LO 23.1) 2. For what arrhythmias are quinidine and lidocaine used? (LO 23.3) 3. What electrolyte ion is active during the plateau phase of the ventricular action potential? (LO 23.2) 4. What pharmacological effect do the Class 1 antiarrhythmic drugs have in common? (LO 23.3) 5. What is cinchonism? (LO 23.3) 6. Describe the procedure for the administration of lidocaine. (LO 23.3, 23.7) 7. Explain the mechanism of action of propranolol. (LO 23.4) 8. What is a special consideration when administering lidocaine by IV drip? (LO 23.7) 9. Explain two important effects of verapamil on the cardiovascular system. (LO 23.6) 10. What are the adverse effects associated with amiodarone? (LO 23.5)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. Mr. Wise is a 75-year-old, otherwise healthy male who was admitted to the hospital for a total right knee replacement. On postoperative day 2, a ventricular arrhythmia was diagnosed. The cardiologist was consulted and prescribed Norpace 150 mg QID. On the fourth day postoperatively, Mr. Wise complains he cannot urinate and is ordered by the house physician to be catheterized. The house physician asks what medications the patient is on. What do you think the physician is thinking about the cause of the urinary difficulties? (LO 23.3) 2. You are working in a pulmonologist’s office when a patient comes in for a refill prescription on her Proventil inhaler, which she uses as needed for her asthma. She mentions that her asthma seems to have worsened over the past couple of months. Upon reading her chart, you notice that she was referred to a cardiologist 3 months ago. While waiting for the physician to approve the refill, you ask what the cardiologist said. The patient states that the cardiologist started her on propranolol for an irregular heartbeat. Is this important information to tell the pulmonologist? Explain. (LO 23.4)
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Chapter Review Continued 3. Mr. Able has been taking verapamil for treatment of his hypertension. At a recent checkup his family physician noticed that Mr. Able had sustained tachycardia. The physician asks you to get some of those free samples of propranolol that were dropped off by the drug sales representative. Could there be a potential problem if the patient takes these two drugs together? (LO 23.4, 23.6)
Multiple Choice Use your critical-thinking skills to answer the following questions. 1. Select the ion movement that is associated with depolarization of ventricular muscle. (LO 23.1) A. Na ions move out of the cell B. K ions move out of the cell C. Na ions move into the cell D. Ca ions move into the cell 2. According to Vaughn-Williams, procainamide is classified as Class (LO 23.3) A. IA B. IB C. IC D. II 3. The antiarrhythmic drug with the shortest duration of action that is administered IV in the emergency treatment of supraventricular tachycardia is (LO 23.6) A. lidocaine B. adenosine C. propranolol D. amiodarone 4. Ataxia, pulmonary fibrosis, skin discoloration, and thyroid disturbances are potential adverse effects of (LO 23.5) A. verapamil B. procainamide C. amiodarone D. disopyramide 5. The pharmacologic effects of verapamil include (LO 23.4) A. decreased heart rate B. decreased force of myocardial contraction C. slowed AV conduction D. all statements are true
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Select all of the ions that regulate heart activity. (LO 23.1) A. Cl B. Ca C. Na D. K
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2. A class IB antiarrhythmic drug does which of the following? (LO 23.3) A. moderate decrease in Phase 0 depolarization B. prolongation of ventricular repolarization C. decrease in AV conduction D. increase in PR interval 3. Which of the following are types of supraventricular arrhythmias? (LO 23.1) A. premature atrial contractions B. premature ventricular contractions C. paroxysmal atrial tachycardia D. atrial flutter 4. Select the actions of beta-blockers. (LO 23.4) A. decrease heart rate B. increase AV conduction C. decrease automaticity of atrial muscle D. increase automaticity of SA nodes 5. Select the adverse effects of amiodarone (LO 23.5) A. pulmonary fibrosis B. torsade de pointes C. blue-gray skin discoloration D. corneal microdeposits
Sequencing Place the following in order of least beats per minute to greatest beats per minute. (LO 23.1) __________________
__________________
__________________
Least
__________________ Greatest
atrial flutter sinus bradycardia atrial fibrillation supraventricular tachycardia
Classification Place the following medications under the correct antiarrhythmic class. (LO 23.3) flecanide
lidocaine
disopyramide
esmolol
ibutilide
quinidine
verapamil
mexiletine
propranolol
dofetilide
diltiazem
propafenone IA
IB
IC
II
III
IV
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Chapter Review Continued Documentation Using the following symptoms observed during a hospital admission, answer the following questions. (LO 23.1, 23.3, 23.4, 23.5) Symptoms Heart rate of 375 beats per minute ECG atrial waves look like a “bag of worms” a. b. c. d.
What type of arrhythmia is the patient suffering? What other conditions might be of concern? What types of medications would be best for short-term treatment of this patient? Is there a recommendation for chronic treatment of this disorder?
Labeling Fill in the missing labels. (LO 23.2)
+30 mV
1 2
0 mV
0 3
4 290 mV
For interactive animations, videos, and assessment, visit:
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Chapter 24
Antianginal Drugs DRUG CLASS AT A GLANCE OTC
NO
PRESCRIPTION
YES
SCHEDULED DRUGS NO FDA PREGNANCY CATEGORY
B, C
INDICATIONS Angina pectoris, coronary artery disease (CAD)
KEY TERMS angina pectoris: chest pain due to decreased blood flow (ischemia) to the heart. atherosclerosis: fatty degeneration of arteries due to accumulation of cholesterol plaques. coronary artery: artery that supplies blood flow to the heart. coronary artery disease (CAD): condition due to atherosclerosis and insufficient blood flow to the heart. exertional angina: angina pectoris caused by increased physical exertion. ischemia: insufficient blood flow to a tissue. variant or Prinzmetal angina: angina pectoris caused by vasospasm of the coronary arteries.
Learning Outcomes
After studying this chapter, you should be able to
24.3 explain the mechanism of action of betablockers in the treatment of angina and CAD.
24.1 describe the main types of angina pectoris and the usual cause of each type.
24.4 recognize the pharmacologic effects produced by the different calcium channel blockers.
24.2 discuss the mechanism of action of the nitrate drugs and compare routes of administration and onset of action of the different nitrate preparations.
24.5 discuss the preferred therapies for the different types of angina.
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Introduction
The coronary arteries branch off the aorta immediately after leaving the heart and deliver blood to the myocardium (Figure 24.1). The coronary arteries are very susceptible to the development of fatty deposits, commonly referred to as plaque. The fatty substance in plaque is mainly cholesterol. Individuals with high blood cholesterol levels are subject to the formation of these cholesterol-laden plaques that reduce coronary blood flow. Atherosclerosis is the term used to describe the fatty degeneration of the coronary arteries. The reduction in coronary blood flow caused by atherosclerosis is referred to as ischemia. Individuals who develop atherosclerosis and experience cardiac ischemia are classified as having coronary artery disease (CAD). Angina pectoris, described as pain in the chest, is caused by CAD. The pain is due to insufficient blood flow and oxygen supply to the myocardium. Complete blockage of one or more of the coronary arteries results in a myocardial infarction (MI) or heart attack. The treatment of CAD is aimed at reducing the number and severity of anginal attacks, limiting progression of atherosclerosis, and preventing the occurrence of myocardial infarction and possible death. Important nondrug components to the treatment of CAD include diets that limit fat and cholesterol, exercise, elimination of smoking, and weight control. The three classes of drugs used in the treatment of angina pectoris and CAD are the nitrates, beta-adrenergic blockers, and calcium channel blockers.
LO 24.1
CLASSIFICATION OF ANGINA PECTORIS There are several different types of angina pectoris. The most common type is caused by exercise, overexertion, or stress. This type is classified as exertional angina and its occurrence is usually predictable. It is caused by insufficient coronary blood flow due to atherosclerotic plaques. Individuals with this type of angina usually know the activities that will bring on the anginal attack. Stopping the activity and resting often provides some relief. Figure 24.1
Coronary Vessels of the Heart Showing Both the Arterial and Venous Circulation
Superior vena cava Aortic semilunar valve Right atrium
Aortic arch Pulmonary trunk
Posterior interventricular artery Right marginal artery Right ventricle (a)
Aortic arch
Superior vena cava
Pulmonary trunk
Left coronary artery Circumflex artery
Right coronary artery
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The second type of angina is referred to as variant or Prinzmetal angina. The cause is vasospasm of one or more of the coronary arteries. This type of angina is variable because it is unpredictable and can occur at any time, even during sleep. Drugs that relax arterial smooth muscle and produce arteriolar dilation are effective in relieving the vasospasm. Some individuals have both the exertional and variant type of angina. Unstable angina is a more serious condition that usually occurs with advanced coronary artery disease. It usually occurs in coronary arteries that are almost
Left atrium
Right atrium
Posterior vein of left ventricle
Left atrium Left marginal artery Anterior interventricular artery Left ventricle
Middle cardiac vein Small cardiac vein
Into right atrium
Coronary sinus Great cardiac vein Left ventricle
Right ventricle (b)
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completely blocked (Figure 24.2). In this situation there is the risk that blood platelets will become activated and initiate formation of a blood clot that can completely block the artery and cause a myocardial infarction. Unstable angina requires aggressive therapy with antianginal, anticoagulant, and antiplatelet drugs in order to prevent blood clot formation. This is also the point in treatment when various procedures such as angioplasty and coronary artery bypass are considered. LO 24.2
NITRATES The nitrates were once known as coronary dilators, but research has shown that during angina these drugs do not produce significant effects on coronary arteries that are atherosclerotic and hardened by arteriosclerosis. Ischemia itself is a potent vasodilator so that during attacks of angina the coronary arteries are already maximally dilated. The main effect of the nitrates is to produce a general vasodilation of systemic veins and arteries. This reduces cardiac work and oxygen consumption. Reduction of cardiac work and oxygen consumption provides relief of ischemia and pain. The nitrates are used in two ways. First, they are administered during attacks of angina to relieve the intense pain. The most common route of administration is sublingual. The drugs in this group have an almost immediate onset of action, although their duration is short. Second, they are administered prophylactically on a daily basis to prevent attacks of angina.
Figure 24.2 Cross Section of Diseased Coronary Artery
Artery wall
Complicated plaque
Lumen
Mechanism of Action The mechanism of action of these drugs is to relax vascular smooth muscle. This effect is caused by nitrate ions, which are enzymatically released from nitrate drugs. These nitrate ions are converted by enzymes in blood vessels to nitric oxide (NO). Nitric oxide is a potent vasodilator that relaxes vascular smooth muscle. Venodilation (dilation of veins) is greater than arteriolar dilation at the lower dosage ranges of these drugs. The main effects produced by vasodilation are a decrease in venous return to the heart (decrease in preload) and a decrease in blood pressure (decrease in afterload). Consequently, cardiac work is reduced. With a reduction in cardiac work, less oxygen is required by the heart, and relief of pain is accomplished. In the vasospastic form of angina, the vasodilating effect of the nitrates is effective in relieving vasospasm of the coronary arteries.
Clinical Use of Nitrate Drugs Nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate are the three available nitrate drugs used to treat angina and CAD. They can be administered in several different forms. Table 24:1 summarizes the different nitrate preparations and their durations of action.
Sublingual Nitroglycerin Nitroglycerin is available as a sublingual tablet and as a sublingual spray for relief of acute anginal attacks. Patients place the nitroglycerin tablet under the tongue and allow the tablet to dissolve without swallowing. Use of the sublingual pump involves one or two sprays under the tongue. The effects of sublingual administration usually occur within 1 to 3 minutes, with the peak effect occurring at about 5 minutes. The duration of action is approximately 30 minutes. Sublingual administration avoids first-pass metabolism by the liver. This method of administration provides the fastest relief for acute angina.
Nitroglycerin Ointment 2% The ointment is applied topically to an area of the chest or abdomen and is covered with a plastic dressing. Absorption occurs through the skin, with an onset of action of 30 minutes and a duration of 4 to 8 hours, depending on the amount applied. Each inch of ointment squeezed from the tube contains approximately 15 mg of nitroglycerin. Nitroglycerin ointment is used prophylactically to prevent the occurrence of angina.
Nitroglycerin Extended-Release Capsules A plague has reduced the lumen to a very small space that can easily be blocked by formation of a blood clot or by vasospasm.
Nitroglycerin is available in capsules of 2.5, 6.5, and 9.0 mg that release the drug gradually over a prolonged period. Duration of action is 8 to 12 hours. The Chapter 24 • Antianginal Drugs
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Note to the Health Care Professional Instruct patient to always sit down before administering sublingual nitrate preparations as sudden drops in blood pressure may cause fainting. Also advise patient to rest for a while after taking the drug. Advise patient not to swallow for several minutes following administration of sublingual nitrate preparations so that the drug can be absorbed from under the tongue. Instruct patient to seek medical assistance if there is no relief of the angina after drug treatment.
period. Transdermal use is indicated for the prevention of angina. Continuous daily exposure to nitrates, especially throughout the 24-hour period, can lead to rapid development of drug tolerance. It is recommended that there should be a 10- to 12-hour drug-free period each day. Consequently, patients who use the transdermal patch are advised to remove the patch at night during sleep.
Nitroglycerin for Intravenous Infusion Nitroglycerin can be administered intravenously in emergency and surgical situations in the hospital. The onset of action is rapid, but the duration of action of IV nitroglycerin is short and drug effects quickly wear off once the infusion is stopped.
Adverse Effects
extended-release capsules are used daily to prevent the occurrence of anginal attacks (prophylaxis).
Transdermal Nitroglycerin (Transderm-Nitro) This nitroglycerin is contained within an adhesive patch that is applied on the torso. The nitroglycerin is slowly and uniformly released into the bloodstream over a 24-hour
The main adverse effects of the nitrates are related to the vasodilating action. Cutaneous flushing, dizziness, headache, weakness, and fainting may be experienced. Sudden or excessive drops in blood pressure can cause reflex tachycardia.
Patient Education Since anginal attacks are unpredictable, it is important for patients to carry the prescribed medication at all times. Nitroglycerin is volatile, and tablets lose potency
Table 24:1
Nitrate Drugs Used in Angina Pectoris and Coronary Artery Disease Common dosage
Onset (min)
Duration (hr)
2.5-, 5-, 10- mg sublingual tablets 5-, 10-, 20-, 30-, 40- mg tablets 40- mg CR tablets, capsules 5-, 10- mg chewable tab
2–5 30 30 30
2–3 4–6 8–12 2–3
Isosorbide mononitrate (ISMO) (Imdur)
20- mg tablets 30-, 60-, 120- mg ER tablets
30 30
6–8 12
Nitroglycerin (Nitrostat) (Nitrolingual Pump Spray) (NitroBid IV ) (Nitro-bid ) (Transderm-Nitro) (Nitrogard)
0.3-, 0.4-, 0.6- mg sublingual tablets 0.4 mcg per spray 5- mcg/min IV infusion 2% ointment 0.2–0.4- mg/hr transdermal patch 1-, 2-, and 3- mg extended-release buccal tablets
1–3 1–3 1–3 30 30 30
30 min 30 min — 4–8 24 6–8
Drug (Trade Name) Isosorbide dinitrate
(Isordil)
(Sorbitrate)
Abbreviations: CR—controlled release, ER —extended release.
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if exposed to air or light. Therefore, it is important that tablets be carried in light-resistant, airtight containers. Also, standard practice is not to use nitroglycerin tablets that are more than 6 months old since there may be significant loss of potency. When patients experience angina, they should be instructed to sit down, place a nitroglycerin tablet under the tongue, and allow it to dissolve without swallowing. Relief should occur within 5 minutes. If it does not, they should repeat the process with another tablet. If there is no relief after three tablets, patients should notify the physician or seek medical assistance. Patients should be aware of the common side effects, such as cutaneous flushing, headache, and dizziness. They should be advised to lie down if they feel faint. These effects are expected and only last for a few minutes. In addition, patients should become aware of the activities that cause angina (overexertion, emotional upset, or overeating) and try to avoid these situations if possible. LO 24.3
BETA-ADRENERGIC BLOCKING DRUGS The beta-blockers antagonize or reverse the effects of sympathetic activation caused by exercise and other physical or mental exertions. In the heart, sympathetic
stimulation (beta-1 receptors) increases heart rate, force of myocardial contractions, and oxygen consumption. The therapeutic action of beta-blockers in the treatment of angina lies in the ability of these drugs to decrease heart rate and force of contractions. These changes decrease cardiac work and therefore oxygen consumption. Decreasing oxygen consumption often prevents development of myocardial ischemia and pain. Beta-blockers are indicated for the long-term (chronic) management of angina pectoris. Patients taking beta-blockers usually have less frequent anginal attacks or a delayed onset of pain during physical exertion. This is another way of saying that they have increased work capacity or exercise tolerance. While all beta-blockers decrease cardiac work and oxygen consumption, propranolol and the drugs listed in Table 24:2 are usually the preferred beta-blockers for the treatment of angina and CAD. Beta-blockers can be used in combination with nitrates in patients who require more than one drug to control angina. When used in combination with nitrates, blockade of beta-1 receptors will usually prevent the reflex tachycardia that may occur with the nitrates. Adverse effects of beta-blockers include drowsiness, tiredness, and GI disturbances such as nausea and diarrhea. Excessive drug dosage can cause bradycardia, hypotension, and possible development of heart failure.
Table 24:2
Beta-Adrenergic Blocking Drugs Used in CAD Drug (Trade Name)
Main uses
Daily dosage range
Nadolol (Corgard)
Angina pectoris, hypertension
80–240 mg PO
Propranolol (Inderal, Inderal LA)
Angina pectoris
80–320 mg PO
Hypertension, migraine
80–240 mg PO
Arrhythmias
40–120 mg PO
Life-threatening arrhythmias
1–3 mg IV
Post-myocardial infarction
180–240 mg PO
Atenolol (Tenormin)
Angina pectoris, hypertension
50–100 mg PO
Metoprolol (Lopressor, Toprol XL)
Angina pectoris, hypertension
100–400 mg PO
Nonselective blockers
Selective beta-1 blockers
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Nonselective beta-blockers, like propranolol, should not be given to individuals with asthma or COPD. Blockade of beta-2 receptors in the respiratory tract can cause bronchoconstriction. The pharmacology of the betablockers was previously discussed in Chapter 6. LO 24.4
CALCIUM CHANNEL BLOCKERS Mechanism of Action The most important action of calcium channel blockers in the treatment of angina and CAD is to block the influx of calcium ions into vascular smooth muscle. Contraction of vascular smooth muscle is very dependent on calcium influx (movement from extracellular to intracellular sites), which normally occurs during membrane depolarization (action potential) of smooth muscle. At the doses used in angina, the calcium channel blockers relax arterial smooth muscle and have little effect on veins. The primary effect is arteriolar vasodilation and reduction of blood pressure. This reduces cardiac work (afterload) and oxygen consumption. The calcium channel blockers are primarily taken on a daily basis to prevent angina and are also the preferred drugs for treatment of variant or Prinzmetal angina. They are the most effective drugs to relieve vasospasm.
In addition to arteriolar dilation, two of the calcium channel blockers, verapamil and diltiazem, also block the influx of calcium ions in cardiac muscle and in the SA and AV nodes. As previously discussed in Chapter 23 with the antiarrhythmic drugs, these actions decrease heart rate, AV conduction, and the force of myocardial contraction. The cardiac actions of verapamil and diltiazem also reduce cardiac work and can contribute to the antianginal effect. The remaining calcium channel blockers are arterial dilators with very little direct actions on the heart. Table 24:3 summarizes the calcium channel blockers and their cardiovascular indications.
Verapamil (Calan, Isoptin) Verapamil is used to treat supraventricular arrhythmias (see Chapter 23). In addition, its vasodilating properties allow it to be considered for the treatment of angina. Because of its prominent effects on the heart, verapamil also can decrease heart rate, AV conduction, and the force of myocardial contraction. These actions decrease cardiac work and oxygen consumption. However, excessive depression of cardiac function can precipitate heart failure.
Diltiazem (Cardizem) The vasodilating and cardiac effects of diltiazem are similar to those of verapamil. However, diltiazem is considered to have slightly less cardiac depressant effects but greater vasodilating actions than verapamil.
Table 24:3
Calcium Channel Blocking Drugs Drug (Trade Name)
368
Cardiovascular actions
Main clinical uses
Verapamil (Calan, Calan SR)
Arterial vasodilation, decreased HR, AV conduction, and myocardial contraction
Angina pectoris, cardiac arrhythmias, hypertension
Diltiazem (Cardizem, Cardizem SR)
Same as above
Same as above
Amlodipine (Norvasc)
Arterial vasodilation
Angina pectoris, hypertension
Felodipine (Plendil)
Arterial vasodilation
Hypertension
Isradipine (Dynacirc, Dynacirc CR)
Arterial vasodilation
Hypertension
Nicardipine (Cardene, Cardene SR)
Arterial vasodilation
Angina pectoris, hypertension
Nifedipine (Procardia, Procardia XL)
Arterial vasodilation
Angina pectoris, hypertension
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Nifedipine (Procardia) Nifedipine has very little effect on heart rate and myocardial contraction, but it is a very potent arterial vasodilator that lowers blood pressure (decreases afterload) and causes relaxation of coronary artery spasm.
channel blockers or beta-blockers since both drug classes are effective in the treatment of hypertension. If there is increased sympathetic activation, then beta-blockers would be the better choice. If combination therapy is required, it should be guided by patient response.
Nicardipine (Cardene)
Variant or Prinzmetal Angina
Nicardipine is similar to nifedipine in that the main pharmacological effects are vasodilation and relaxation of coronary artery spasm.
Vasospasm is the major feature of this type of angina. The calcium channel blockers, which relax arterial smooth muscle, are the preferred drugs. The nitrates are also effective. However, chronic use of nitrates requires a drug-free interval, usually at night, in order to avoid drug tolerance. Consequently, the patient would not be protected from vasospasm during this period. The combination of a calcium blocker and nitrate is often the preferred choice when additional treatment is required.
Other Calcium Antagonists Amlodipine (Norvasc), felodipine (Plendil ), and isradipine (DynaCirc) are additional calcium antagonists. These drugs have little or no direct actions on the heart and are primarily arterial vasodilators with actions and adverse effects similar to nifedipine.
Adverse Effects Common adverse effects of the calcium antagonists include headache, facial flushing, dizziness, hypotension, and minor gastrointestinal (GI) disturbances. Constipation is one of the more common side effects of verapamil. The calcium channel blockers that do not have direct cardiac effects, like nifedipine, are potent vasodilators that can cause reflex tachycardia if blood pressure drops below normal. With overdosage, verapamil and diltiazem can cause bradycardia, AV block, and decreased myocardial contraction that can lead to heart failure. The use of either verapamil or diltiazem with beta-blockers is generally contraindicated; the combination can cause excessive cardiac depression and heart failure.
Unstable Angina Patients with unstable angina are at serious risk of developing a myocardial infarction. Antiplatelet and anticoagulant therapy is essential to prevent formation of a blood clot at the site of arterial blockage. This also is the point when coronary artery bypass grafting or percutaneous coronary interventions, such as stent implantations, are considered. While antianginal drugs are useful for prevention of anginal attacks, the patient needs to reevaluate lifestyle, diet, lipid profile, exercise, and smoking habit in order to prevent progression of disease.
Patient Administration and Monitoring
LO 24.5
PREFERRED THERAPY FOR TREATMENT OF ANGINA PECTORIS
Monitor vital signs when these drugs are administered during the treatment of acute angina.
All patients with CAD should carry with them one of the sublingual nitrate drugs for immediate treatment of a sudden attack of angina.
Explain to patient the common side effects of the drugs that dilate blood vessels: dizziness, headache, flushing, faintness, nausea.
Exertional, Fixed, or Stable Angina The nitrates, beta-blockers, and calcium channel blockers are all very effective in controlling the exertional type of angina. The choice often depends on other cardiovascular conditions that the patient may have. For example, patients with hypertension are best treated with calcium
Instruct patient on the proper self-administration of sublingual nitroglycerin or similar preparations.
Instruct patient to report excessive changes in blood pressure and pulse rate, or other significant changes. Explain to patient the importance of weight control, diets low in fats and cholesterol, eliminating smoking, and exercise if approved by the physician. Help patient to identify the situations or stresses that trigger angina and establish mechanisms for avoidance.
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Chapter Review Understanding Terminology Answer the following questions. 1.
What are two main types of angina pectoris? How do they differ? (LO 24.1)
2.
Write a short paragraph using the following terms: coronary arteries, atherosclerosis, angina pectoris, exertional angina, and vasospastic angina. (LO 24.1)
Acquiring Knowledge Answer the following questions. 1. What is the mechanism of action of the nitrates? (LO 24.2) 2. What are the different routes of administration for nitroglycerin? When is each indicated? (LO 24.2) 3. Explain the mechanism of action of propranolol in the treatment of angina. (LO 24.3) 4. What is the effect of the calcium channel blockers on vascular smooth muscle? (LO 24.4) 5. Compare the adverse effects of the nitrates and the calcium channel blocker drugs. (LO 24.2, 24.4)
Applying Knowledge on the Job Use your critical-thinking skills to answer the following questions. 1. While doing your afternoon assessment of your patients in cardiac care, you ask Mr. Horn if he has had a bowel movement today. He states he has not moved his bowels in 3 days. You review the chart and see that 4 days ago, on admission, he was started on Lasix, Transderm-Nitro patch, verapamil, and a potassium supplement. Which drug is most likely causing the constipation? (LO 24.4) 2. Mrs. George was just started on Procardia and Nitro-Bid upon her admission to the cardiac care unit. She has also just been allowed to get out of bed. What precautions might you give her? (LO 24.2, 24.4) 3. Instruct Mrs. Smith (or one of your classmates) on the proper procedure for administering sublingual nitroglycerin. What should she do if the first tablet does not provide relief? Second tablet? Third tablet? (LO 24.2) 4. Prepare a short oral presentation for a patient with unstable angina that describes the various nondrug modalities that are important to halt progression of the disease. (LO 24.5)
Multiple Choice Use your critical-thinking skills to answer the following questions. 1. The nitroglycerin dosage form providing the longest duration of action is (LO 24.2) A. sublingual nitroglycerin tablets B. nitroglycerin ointment C. transdermal nitroglycerin D. IV nitroglycerin (bolus injection) 2. The therapeutic actions of propranolol to prevent anginal attacks include (LO 24.3) A. decreased heart rate B. reduced force of myocardial contraction
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C. decreased oxygen consumption D. all statements are true 3. The pharmacologic actions of verapamil include (LO 24.4) A. decreased AV conduction B. increased myocardial contraction C. decreased heart rate D. only A and C are true 4. In the treatment of variant angina, the drug that is an arterial dilator without direct effects on the heart is (LO 24.4) A. nitroglycerin B. metoprolol C. nifedipine D. verapamil 5. The drug that is best described as a venodilator that decreases preload (venous return) in the treatment of angina is (LO 24.2) A. propranolol B. verapamil C. nifedipine D. isosorbide dinitrate
Multiple Choice (Multiple Answer) Select the correct choices for each statement. The choices may be all correct, all incorrect, or any combination. 1. Angina pectoris is caused by which of the following? (LO 24.1) A. insufficient blood flow B. lack of oxygen to the myocardium C. decreased heartbeat D. reduction of cardiac work 2. The main mechanisms of action of nitrates include (LO 24.2) A. increasing the venous return to the heart B. reducing atherosclerosis in the arteries C. increasing cardiac work and oxygen consumption D. relaxation of systemic veins and arteries 3. Beta-blockers work by doing which of the following? (LO 24.3) A. decreasing heart rate B. decreasing cardiac work C. decreasing force of contractions D. decreasing oxygen consumption 4. Select all of the different types of angina. (LO 24.1) A. nystagmic B. unstable C. Prinzmetal D. exertional
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Chapter Review Continued 5. Variant angina is treated with what types of medication? (LO 24.5) A. calcium channel blockers B. beta-blockers C. nitrates D. anticoagulants
Sequencing Place the following in order of longest duration of action to shortest duration of action. (LO 24.2) _________________
_________________
_________________
_________________
Longest
Shortest
Nitro-Bid ointment Nitrostat Isordil CR tablets Sorbitrate
Classification Place the following medications under the disease they are used to treat. (LO 24.5) beta-blockers nitrates antiplatelets anticoagulant calcium channel blockers Stable angina
Variant angina
Unstable angina
Matching Match the following mechanisms of action with the corresponding class of drug. Answers may be used more than once. (LO 24.2, 24.3, 24.4) a. beta-blocker b. nitrate c. calcium channel blocker 1. 2. 3. 4. 5. 6.
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___ ___ ___ ___ ___ ___
relax vascular smooth muscle decrease heart rate decrease in venous return decrease in blood pressure decrease force of contraction relax arterial smooth muscle
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Documentation Using the prescription below, answer the following questions. (LO 24.2)
Riverview Cardiology Practice RX 12345 Main Avenue Anytown, USA 12345 931-555-1000 NAME:
Doug Coronado
DATE:
ADDRESS: RX
Isosorbide dinitrate 2.5mg
Sig:
Take one tablet by mouth as directed
Dr. Craig River
M.D.
Substitution Permitted DEA #:
a. b. c. d.
M.D. Dispense as written REFILL:
NR
1
2
3
4
What type of angina is being treated with this drug? In this milligram strength, what is the likely dosage form? What is the onset of this particular medication? Are there other medications that could be used to treat this type of angina? If so, what are they?
For interactive animations, videos, and assessment, visit:
www.mcgrawhillconnect.com Chapter 24 • Chapter Review
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5 PART
Pharmacology of the Vascular and Renal Systems CHAPTER 25 Diuretics 376
CHAPTER 26 Antihypertensive Drugs 398
CHAPTER 27 Anticoagulants and Coagulants 415
CHAPTER 28 Nutrition and Therapy 436
CHAPTER 29 Hypolipidemic Drugs
459
CHAPTER 30 Antianemics 480
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Chapter 25
Diuretics DRUG CLASS AT A GLANCE OTC caffeine
YES
PRESCRIPTION
YES
SCHEDULED DRUGS
NO
FDA PREGNANCY CATEGORY
B, C
INDICATIONS Edema, congestive heart failure, hypertension, renal disease
KEY TERMS acidification: process that alters the pH to less than 7. acidosis: pH less than 7.45 or a condition in which the tissues have relatively more acid or acid waste than normal. alkalosis: pH greater than 7.45 or a condition in which the tissues have less acid than normal. anuria: condition in which no urine is produced. aquaporins: specialized proteins that form pores (channels) in the cell membrane that allow water to pass through but not small molecules like ions. aquaresis: renal excretion of water without electrolytes. aqueous humor: ocular fluid; watery substance that is located behind the cornea of the eye and in front of the lens. ascites: excess fluid in the space between the tissues lining the abdomen and abdominal organs (the peritoneal cavity), usually associated with organ failure. convoluted: coiled or folded back on itself. distal convoluted tubule (DCT): part of the nephron that is closest to the collecting duct. diuresis: condition that causes urine to be excreted, usually associated with large volumes of urine. edema: swelling caused by fluid in body tissue.
euvolemia: state of normal body fluid volume. extracellular: area outside the cell. hyperchloremia: abnormally high level of chloride ions circulating in the blood. hypertonic: a condition where the concentration of salt (sodium, electrolytes) is greater than that found inside the cells. hypochloremia: abnormally low level of chloride ions circulating in the blood. hypokalemia: abnormally low level of potassium ions circulating in the blood. hyponatremia: abnormally low level of sodium ions circulating in the blood. hypotonic: a condition where the concentration of salt (sodium, electrolytes) is less than that found inside the cells.
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metabolic waste products: substances formed through the chemical processes that enable cells to function; usually, these substances are excreted by the body. miotic: a drug that causes constriction of the pupil of the eye. nephritis: inflammation of the glomeruli often following a streptococcus infection. oliguria: condition in which very small amounts of urine are produced. osmolality: the concentration of particles dissolved in a fluid. osmoreceptors: specialized cells in the hypothalamus that respond to changes in sodium concentration (osmolarity) in the blood. proximal convoluted tubule (PCT): part of the nephron that is closest to the glomerulus. refractory: unable to produce an increased response even though the stimulation or amount of drug has been increased. tubular reabsorption: process in which the nephrons return to the blood substances (ions, nutrients) that were filtered out of the blood at the glomerulus. tubular secretion: process in which the nephrons produce and release substances (ions, acids, and bases) that facilitate sodium ion reabsorption and maintain acid-base balance. uremia: accumulation of nitrogen waste materials (for example, urea) in the blood.
Learning Outcomes
After studying this chapter, you should be able to
25.5 explain how the action of each diuretic differs from that of thiazide diuretics.
25.1 explain the role of the kidneys in water excretion.
25.6 explain what happens when a diuretic becomes refractory.
25.2 describe the difference between renal filtration and renal reabsorption.
25.7 explain how diuretics affect organs like the eye and liver.
25.3 identify two areas of the renal tubules where sodium and water transport are connected.
25.8 describe three major side effects of each diuretic.
25.4 explain the function of the kidney in maintaining acid balance.
25.9 explain the clinical use and clinically significant terms associated with diuresis and diuretics.
Introduction
The primary functions of the kidneys are to maintain water, electrolyte, and acid-base balance. In order to accomplish this, the kidneys receive a large portion of the cardiac output (25 percent). As blood flows through the kidneys, substances are constantly filtered from the blood. Large molecules, such as plasma proteins, cannot pass through renal membranes, so only small molecules (ions, water, and glucose) and cell waste products are cleared from the blood. The body requires ions and water to function. For example, electrolytes—sodium (Na1), potassium (K1), and chloride (Cl2)—preserve the stability of cell membranes, whereas bicarbonate ions (HCO32) buffer the blood to maintain the pH at 7.35–7.45. Therefore, the kidneys must reabsorb the essential elements and eliminate the waste products. This balance between renal reabsorption and excretion results in the formation of urine. When this balance is altered by disease or circumstance, the kidneys cannot process essential ions and water and fluid accumulate in the body tissues.
Chapter 25 • Diuretics
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LO 25.1 1
LO 25.7 7
LO 25.9
CLINICAL INDICATIONS AND RENAL FUNCTION Diuretics are primarily used in the management of anuria, hypertension, and edema. These are conditions in which the kidneys have stopped making urine (anuria), or there is an accumulation of fluid in other tissues (edema). For example, CHF and liver cirrhosis are associated with an accumulation of fluid in body tissues as a result of acute or chronic organ disease. Edema also may result from local inflammation in the brain, eyes (glaucoma), and kidneys (nephritis). As long as the kidneys are functioning, urine production and renal water excretion can be stimulated in order to eliminate the accumulated fluid. This is accomplished either by increasing the blood flow to the kidneys (glomerular filtration) or by decreasing the renal reabsorption of water. Some diuretics stimulate urine production by increasing glomerular filtration. Other diuretics reduce the excess fluid associated with hypertension and edema by decreasing renal sodium and water reabsorption. As water reabsorption decreases, urine volume and flow increase (diuresis). There are six classes of diuretics: osmotic agents, carbonic anhydrase inhibitors, thiazide and thiazide-like compounds, organic acids, potassium-sparing diuretics,
and ADH antagonists ( Table 25:1). Each of these classes of diuretics produces diuresis by inhibiting water and/or sodium ion reabsorption in the kidneys. Because these drugs inhibit water reabsorption at different sites along the nephrons, the intensity of the diuresis varies with each class of drugs. In general, the intensity of diuresis is dependent upon the extent to which sodium ions are excreted into the urine. To know which drugs are the most effective diuretics and which adverse effects result from the diuretic action, one needs to have an idea of how the renal tubules in the kidneys work. LO 25.1 1
LO 25.2
LO 25.3 3
LO 25.4 4
LO 25.9
RENAL PHYSIOLOGY Urine formation is essential for normal body function because it enables the blood to reabsorb necessary nutrients, water, and electrolytes. In addition, metabolic waste products are eliminated from the body through the urine. These processes take place in the working units of the kidneys known as the nephrons. The kidneys contain millions of nephrons, and each nephron is composed of several segments: the glomerulus, the proximal convoluted tubule (PCT), the loop of Henle, the distal convoluted tubule (DCT), and the
Table 25:1
Classes of Diuretics Class
Drugs
Adverse effects*
Carbonic anhydrase inhibitors
Acetazolamide, methazolamide
Anorexia, drowsiness, GI distress, headache, metabolic acidosis
Organic acids (loop diuretics)
Bumetanide, ethacrynic acid, furosemide, torsemide
Hyperglycemia, hypokalemia, hypotension, tone deafness
Osmotic (lumenal) diuretics
Glycerin, isosorbide, mannitol, urea
Chills, dizziness, headache, nausea, strain on cardiac function (plasma volume expansion), vomiting
Potassium-sparing diuretics
Amiloride, eplerenone, spironolactone, triamterene
Gynecomastia**, hyperkalemia, nausea, vomiting
Thiazide and thiazide-like diuretics
Chlorothiazide, chlorthalidone, hydrochlorothiazide, hydroflumethiazide, indapamide, methychlothiazide, metolazone
Dizziness, headache, hyperglycemia, hyperkalemia, hyperuricemia, hypotension, lightheadedness, nausea
Xanthine derivatives (active ingredients of over-the-counter diuretic products)
Caffeine, pamabrom, theobromine, theophylline
Diarrhea, insomnia, irritability, nervousness, restlessness, tachycardia
* This is not a comprehensive list of adverse effects. Adverse effects are presented in alphabetical order and not according to any order of incidence. The most clinically significant adverse effects are bolded. ** Spironolactone only.
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Figure 25.1 Nephron Showing the Glomerulus, the Proximal Convoluted Tubule (PCT), Nephron Loop (Loop of Henle), the Distal Convoluted Tubule (DCT), and Collecting Duct
C o r t e x
Tubular Reabsorption PCT DCT
Vasa recta
M e d u l l a
plasma proteins do not. The remaining segments (renal tubules) are involved with reabsorption and secretion. The proximal tubule, loop of Henle (nephron loop), and distal tubule contain specialized transport systems that pull ions out of the tubule lumen and transport them back into the blood (tubular reabsorption). One of the most important tubular reabsorption mechanisms is the transport of sodium ions into the circulation. These segments also secrete substances (ions, acids, and bases) that facilitate sodium ion reabsorption and maintain acid-base balance (tubular secretion).
Collecting duct
Nephron loop
Most of the ions and nutrients that are filtered at the glomerulus are reabsorbed by the renal tubules. The renal tubules reabsorb as much sodium as possible (99 percent). Sodium ions are extremely important because they are the principal cations (positively charged ions) in the extracellular fluid, and their large extracellular concentration creates an osmotic gradient that attracts water molecules. Thus, the renal mechanism for water conservation (balance) is directly dependent upon the tubular reabsorption of sodium ions. Along the nephron, sodium ions are reabsorbed by two mechanisms: cation exchange and chloride ion transport. In the proximal and distal convoluted tubules, sodium ions (Na1) are reabsorbed in exchange for hydrogen ions (H1). Hydrogen ions are produced in the tubular cells through the action of the enzyme carbonic anhydrase (CAH). In the presence of this enzyme, carbon dioxide (CO2) and water (H2O) combine to form carbonic acid (H2CO3). Carbonic acid rapidly breaks down into hydrogen ions (H1) and bicarbonate ions (HCO32). See Figure 25.3. ⎯ H2CO3 → HCO32 1 H1 CO2 1 H2O ← ⎯→ CAH
The vasa recta is a network of blood vessels that serves each nephron.
collecting duct (Figure 25.1). Urine is produced in the nephrons through the processes of filtration, reabsorption, and secretion.
Filtration Filtration of substances from the blood into the nephrons occurs in the glomerulus. The blood pressure entering the glomerulus is high compared to the pressure within the glomerulus, which facilitates movement of small molecules and fluid into the glomerular filtrate. As shown in Figure 25.2, vitamins, amino acids, and electrolytes pass into the glomerular filtrate (which ultimately becomes urine), but large molecules like RBCs and
The hydrogen ions are secreted by the proximal and distal tubules in exchange for sodium ions (see Figure 25.4). Subsequently, the sodium and bicarbonate ions are transported into the blood. In addition to the hydrogen ion exchange, the distal convoluted tubules secrete potassium ions (K1) in exchange for sodium. The secretion of potassium ions is primarily controlled by the adrenal mineralocorticoid aldosterone. Within these tubules are aldosterone receptors. By interacting with its receptors, aldosterone causes intracellular potassium ions to enter the tubular fluid (urine). As the potassium ions are secreted, sodium ions are reabsorbed (Figure 25.5). In the loop of Henle, sodium ions are reabsorbed, but not through an ion-exchange mechanism. Sodium Chapter 25 • Diuretics
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Figure 25.2
Urine Formation Blood flow
Renal corpuscle
1 Glomerular filtration Creates a plasmalike filtrate of the blood
Flow of filtrate 2 Tubular reabsorption Removes useful solutes from the filtrate, returns them to the blood
Peritubular capillaries
and
Turned back: Blood cells Plasma proteins Large anions Protein-bound minerals and hormones Most molecules > 8 nm in diameter
Tubular secretion Removes additional wastes from the blood, adds them to the filtrate
Renal tubule 3 Water conservation Removes water from the urine and returns it to the blood; concentrates wastes
H2O H2O H2O
Bloodstream
Urine (a)
Endothelial cell of glomerular capillary Basement membrane Filtration slit Filtration pore
Passed through filter: Water Electrolytes Glucose Amino acids Fatty acids Vitamins Urea Uric acid Creatinine Glomerular filtrate
(b)
(a) Basic steps in the formation of urine. (b) Filtration of substances at the glomerular membrane.
ions are reabsorbed in the loop of Henle in conjunction with chloride ions (Cl2). In other words, chloride ions are actively reabsorbed and sodium ions follow (Figure 25.5). When the renal tubules reabsorb sodium ions through these mechanisms, an osmotic gradient is established along the nephron. More sodium ions are present in the blood, and fewer sodium ions are present inside the renal tubules. Therefore, water molecules migrate toward the sodium ions and into the blood (water reabsorption). Water is primarily reabsorbed within the proximal convoluted tubules and the collecting ducts. Under the influence of the pituitary hormone antidiuretic hormone (ADH), the pores (aquaporins) of the collecting ducts open, and water rushes toward the sodium ions. As a result, water is removed from the urine, and urine volume decreases. The renal reabsorption of sodium and water maintains the plasma volume and water balance. 380
It is important to understand the mechanisms of tubular reabsorption of sodium ions because these mechanisms are the basis of diuretic action. Most diuretics increase urine flow (diuresis) by inhibiting the renal tubular reabsorption of sodium ions and water.
Tubular Secretion The major secretory functions of the nephrons involve the tubular secretion of hydrogen ions, potassium ions, weak acids, and weak bases. Part of the tubular secretory process (cation exchange) has already been mentioned, since it directly results in sodium reabsorption. However, the tubular secretion of hydrogen ions serves another important role in the regulation of acid-base balance. This effect is accomplished through acidification of the urine (reducing the pH level to less than 7). Certain renal tubular mechanisms (carbonic anhydrase system) maintain the pH of the blood between 7.35 and 7.45 by altering the pH of the urine. As described,
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Dissociation of Carbonic Acid (H 2 CO 3 ) into Bicarbonate (HCO 3 2 ) and Hydrogen (H 1 ) Ions
Figure 25.3
Renal tubule cells (proximal convoluted tubule)
Blood of peritubular capillary
Tubular fluid Glomerular filtrate NaHCO3
K+ Na+ HCO3 + –
–
HCO3
Na+
Na+
H+
H+
–
HCO3
H+ H2CO3 H2CO3
H2CO3 CAH
CAH
H2O
H2O
H2O + CO2
CO2
CO2
Urine
The H 1 ions are exchanged for sodium ions (Na 1 ) from the tubular fluid so Na 1 are reabsorbed. Formation of (H 2 CO 3 ) is accomplished through the enzyme carbonic anhydrase (CAH).
Figure 25.4
Ion Reasborption in the Proximal Convoluted Tubule
Peritubular capillary
Tissue fluid
Tubule epithelial cells
Glucose Na+ K+ K+
Tubular fluid
Na+ Glucose Na+ H+ Cl– Anions
ATP Na+–K+ pump ADP + Pi
Cl– Tight junction
H2O
Brush border
Sodium–glucose transport protein Na+–H+ exchange (acidifies the urine) Cl––anion exchange Aquaporin
H2O, urea, uric acid, Na+, K+, Cl–, Mg2+, Ca2+, Pi
Water and solutes (glucose) in the tubular fluid (right) are carried through the tubule epithelium by various means including aquaporins and ion exchange.
the carbonic anhydrase system produces hydrogen ions (H1) and bicarbonate ions (HCO32) from CO2 and water. The bicarbonate is transported into the blood, where it neutralizes (buffers) cell waste products, such as lactic acid. As a result, the pH of the blood remains
relatively neutral as long as bicarbonate is available. At the same time, hydrogen ions secreted into the renal tubular fluid acidify the urine (to a pH between 4 and 6). See Figure 25.4. Any condition that impairs the renal production of hydrogen and bicarbonate ions alters the Chapter 25 • Diuretics
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Figure 25.5
Reabsorption and Secretion in the Nephron and Sites of Diuretic Drug Actions Na+ K+ Ca2+ Mg2+ Cl– HCO3– H2O
Glucose Amino acids Protein Vitamins Lactate Urea Uric acid PCT
Na+ Cl– HCO3– H2O DCT
Sites of diuretic action
Sites of diuretic action
Osmotic diuretics: Glycerin, isosorbide, mannitol, urea
Thiazide/thiazide-like diuretics: Chlorothiazide, hydrochlorothiazide, chlorthalidone, metolazone
Carbonic anhydrase inhibitors: Acetazolamide, methazolamide
Urea H+ Uric acid NH4+ Creatinine Some drugs Nephron loop: Descending limb Ascending limb
Loop diuretics: Bumetanide, ethacrynic acid, furosemide, torsemide
H+ K+ NH4+ Na+ K+ Cl– Collecting duct
H2O
Potassium-sparing diuretics: Amiloride, eplerenone, spironolactone, triamterene
ADH antagonist diuretics: Conivaptan
H2O Urea
Urea
Key Tubular reabsorption Tubular secretion
acid-base balance of the body. For example, insufficient bicarbonate production because of carbonic anhydrase inhibition leads to metabolic acidosis. As part of their excretory function, the renal tubules have specialized transport systems that remove weak acids and bases from the blood. Normal cell metabolism produces weak acids (uric acid) and weak bases. Usually, these substances are presented to the kidneys for excretion. The proximal convoluted tubules secrete weak acids and weak bases into the urine. Many drugs are also weak acids (aspirin, barbiturates, and penicillin) or weak bases (opioid analgesics and antihistamines), which also are secreted into the tubular fluid through the proximal convoluted tubules. Metabolic waste products (weak acids, weak bases) compete for the same transport sites that excrete these drugs. This competition can result in altered drug excretion—for example, accumulation in the blood. As long as the kidneys continue to produce urine, the blood is cleared of waste products and toxic (drug) substances. 382
LO 25.1 1
LO 25.2
LO 25.3 3
LO 25.4 4
LO 25.9
CONDITIONS ASSOCIATED WITH RENAL DYSFUNCTION Renal function may be altered by renal disease or cardiovascular dysfunction. Usually, infection or inflammation in the renal tissues (nephritis) reduces renal function. Reduced renal function occurs in glomerulonephritis and pylonephritis. On the other hand, circulatory problems associated with chronic heart failure (CHF), hypertension, and shock decrease renal function by reducing blood flow to the kidneys. Such circulatory disorders are often severe enough to produce renal failure. Whether the renal tissue is damaged or the blood flow is reduced, the ultimate result is decreased urine flow, decreased urine volume (oliguria), or no urine production at all (anuria). As a result, the blood is not adequately filtered, and toxic products and ions accumulate. Such an accumulation can lead to uremia, edema, and hypertension.
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Uremia (toxemia) is an accumulation of nitrogenous waste products in the blood due to impaired renal filtration. Edema and hypertension are associated with fluid (water) retention in the circulatory system, often as a result of insufficient sodium clearance. Fluid accumulates in the extracellular spaces of the body when too much sodium is retained in the circulation and tissue fluid. Circulating sodium ions create an osmotic gradient, which pulls water molecules into the circulation. This action causes the blood volume to expand, producing an increase in blood pressure (hypertension). The same phenomenon occurs with edema, in that water migration into the tissues causes swelling, especially in the legs and feet. The increased fluid retention and pressure put a greater strain on the failing heart and kidneys.
used. These drugs are used to stimulate urine flow in the treatment of anuria and oliguria before irreversible renal damage occurs. Mannitol may be indicated for acute renal failure or in cardiovascular surgeries in which renal function is severely compromised. Increased urine flow is also valuable in the treatment of drug toxicity or overdose. Mannitol-induced diuresis maintains renal function and keeps the flow of dilute urine so that renal excretion of the toxic substance is achieved. Mannitol also is used in the treatment of cerebral edema and glaucoma. Localized swelling, edema, and pressure (intraocular, cerebral) can be reduced with mannitol. The route of administration and low intensity of diuresis produced limit the clinical use of mannitol.
Mechanism of Action LO 25.5 5
LO 25.7 7
LO 25.8 8
LO 25.9
OSMOTIC DIURETICS Clinical Indications Of the osmotic diuretics, glycerin, isosorbide, mannitol, and urea, mannitol (Osmitrol ) is the most frequently
Osmotic diuretics are compounds that can be filtered by the glomerulus but not reabsorbed by the renal tubules. These drugs cannot penetrate cell membranes; they must be given intravenously ( Table 25:2). Once inside the circulation, the drugs act osmotically, attracting fluid from edematous tissues. Since these drugs cannot cross tubular
Table 25:2
Uses and Dose Range of Osmotic Diuretics and Carbonic Anhydrase Inhibitors Drug name (Trade Name)
Use
Adult daily dose
Glycerin (Osmoglyn)
Reduce intraocular pressure; interrupt acute glaucoma attacks (glaucoma)
1–2.0 g/kg (4–6 oz) PO 1–1.5 hr prior to surgery
Isosorbide (Ismotic)
Reduce intraocular pressure; interrupt acute glaucoma attacks (glaucoma)
1–5 g/kg (1–3 g/kg) BID, QID
Mannitol (Osmitrol )
Oliguria
50–100 g in 24hr 15% or 25% solution, IV
Reduce intracranial or intraocular pressure
1.5–2 mg/kg of a 15%, 20%, or 25% solution, IV
Excretion of toxic substances
5–25% solution infused IV (maximum 200 g)
Urologic irrigation
2.5% solution IV
Reduce intracranial or intraocular pressure
1–1.5 g/kg (3.3–5 ml) solution slow IV infusion (maximum 120 g/day)
Glaucoma
250–1000 mg/day PO, IV in divided doses every 4 hr
Edema
250–375 mg PO
Epilepsy
375–1000 mg PO in divided doses
Glaucoma
50–100 mg PO BID, TID
Osmotic diuretics
Urea (Ureaphil) Carbonic anhydrase inhibitors Acetazolamide (Diamox)
Methazolamide
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membranes, osmotic diuretics become trapped in the tubular lumen and create an osmotic gradient within the renal tubule lumen (Figure 25.6). Water molecules tend to migrate toward the diuretic molecules. Consequently, this water is not reabsorbed and is excreted into the urine along with the diuretic. Although water reabsorption is inhibited, there is no majo
